System and method for the detection of gamma radiation from a radioactive analyte

ABSTRACT

A system and method for the measurement of radiation emitted from an in-vivo administered radioactive analyte. Gamma radiation sensors may be used to determine the proper or improper administration of a radioactive analyte, and identify patient administration factors that correlate with improper administration over a set of patients so as to identify administration risk factors to improve administration of radioactive analyte. In some cases, the system employs a sensor having a scintillation material to convert gamma radiation to visible light, which enables embodiments of the sensor to be ex vivo. A light detector converts the visible light to an electrical signal. This signal is amplified and is processed to measure the captured radiation. The sensor enables collection of sufficient data to support separate application to predictive models, background comparisons, or change analysis.

PRIORITY

The present application is a continuation of U.S. application Ser. No.15/885,112 filed on Jan. 31, 2018, which is a divisional of U.S.application Ser. No. 14/678,550 filed on Apr. 3, 2015, now U.S. Pat. No.9,939,533, which is a continuation-in-part of U.S. application Ser. No.13/840,925 filed on Mar. 15, 2013, now U.S. Pat. No. 9,002,438, whichclaims the benefit of priority to U.S. Provisional Application No.61/653,014, filed on May 30, 2012, each of which are hereby incorporatedherein in their entirety.

STATEMENT REGARDING GOVERNMENT SUPPORT

None.

FIELD OF THE INVENTION

The present invention relates to measurement and prediction ofbiological processes, and more particularly to a system and method forusing localized radio-labeled tracer temporal uptake to measure andpredict biological processes, and ensuring the proper injection oradministration of radio-labeled tracer.

BACKGROUND

Oncologists are interested in knowing if the prescribed cancer therapyis having the intended effect, in order to improve outcomes, minimizeside effects, and avoid unnecessary expenses. Cytotoxic treatments killtumor cells. Cytostatic treatments inhibit cell growth leaving tumorsthe same size, but preventing the spread of the disease. Cytostatictreatments inhibit cell growth leaving tumors the same size, butpreventing the spread of the disease. Immunotherapy treatments use thebody's immune system to attack the cancer and initially result in aninflammatory response in the tumor area before there is evidence thatthe body is effectively attacking the tumor. Historically, measuring thetumor has been the primary way for oncologists to assess treatmenteffectiveness; however, we now understand that the size of the tumor isoften not the best or earliest indicator of the therapy effectiveness.With cytotoxic treatment the tumor size reduction only occurs aftercancer cells die and the body's natural processes eliminate dead cells;this process can often take weeks. With cytostatic treatment, cancercells stop growing leaving the clinician unsure of the state of theunderlying cancer. With immunotherapy, the body's inflammatory responseoften masks the tumor from proper evaluation.

The tools available to oncologists and researchers today to assess tumorresponse to treatments are not ideal. Palpating the tumor is easy andinexpensive, but it is limited to tumors close to the surface, relies ona physician's memory and notes, and primarily measures size. The lack ofreproducibility of this palpating process, coupled with historicalreasons, contributed to the initial acceptance of significant changes intumor size as an indicator of therapy assessment. Wolfgang A. Weber, etal., “Use of PET for Monitoring Cancer Therapy and for PredictingOutcome,” 46 J. Nucl. Med. (No. 6) 983-995 (June 2005). Imaging tools(CT, Mill, x-ray) provide more precise measurements for tumors bothclose to the surface and in deep tissue, but again primarily measuresize, not the ideal indicator. Molecular imaging (PET/CT scan) capturesthe positron emissions from injected radio-labeled tracers captured bylive cancer cells and is routinely used for pre-therapy staging ofcancer. Visually identifying metastatic disease is the primary means ofstaging cancer; however, a semi-quantitative PET/CT measurement known asStandardized Uptake Value (SUV) is also being used to stage cancer. Forexample, SUVs are used to help determine whether or not lung nodules aremalignant. SUVs are basically a ratio of the amount of radio-labeledtracer in an area of interest (tumor) compared to the level in the restof the body. While molecular imaging is a primary tool for thepre-therapy need to stage a patient's cancer, it is also rapidlybecoming the most advanced tool for oncologists and researchers toassess tumor response, since molecular imaging can capture the metabolicor proliferative condition of the cancer and the size of the tumor.Using an SUV taken from the PET images acquired approximately 60-minutesafter injection or administration of a radio-labeled tracer in thestaging scans and then comparing this value to an SUV from a follow-upPET/CT is currently the best available indicator for therapyeffectiveness.

Despite the increasing trend to use comparative PET/CT scans inassessing tumor response in more and more cancer types as clinicalevidence continues to grow, there are still limitations with this stateof the art assessment tool. PET/CT scans are expensive and their use isoften challenged. Additionally, there are several issues with SUVcalculations. According to Dr. Dominique Delbeke: “[t]he reproducibilityof SUV measurements depends on the reproducibility of clinicalprotocols, for example, dose infiltration, time of imaging after 18F-FDGadministration, type of reconstruction algorithms, type of attenuationmaps, size of the region of interest, changes in uptake by organs otherthan the tumor, and methods of analysis (e.g., maximum and mean).”Dominique Delbeke, et al., “Procedure Guideline for Tumor Imaging with18F-FDG PET/CT 1.0,” 47 J. Nucl. Med. (No. 5) 885-895 (May 2006).Infiltrated injection (extravasation) of radio-labeled tracer is acomplication that often goes unnoticed by clinicians. Medhat Osman, “FDGDose Extravasations in PET/CT: Frequency and Impact on SUVMeasurements,” Frontiers in Oncology (Vol. 1:41) 1 (2011). Aninfiltration is a common problem that can occur when the radio-labeledtracer infuses the tissue near the venipuncture site, and can resultfrom the tip of the catheter slipping out of the vein or passing throughthe vein. Additionally, the blood vessel wall can allow part of thetracer to infuse the surrounding tissue. As a result, the radio-labeleddose being delivered is inaccurate and thus so are the SUV calculations,which can severely impact patient treatment and research conclusions.These infiltrations may in fact contribute to the wide variability inresearcher's efforts to characterize SUV thresholds for clinicaldecision making. In one study, it was determined that the “thresholdsfor metabolic response in the multicenter multiobserver non-QA settingswere −34% and 52% and in the range of −26% to 39% with centralized QA”.Linda M. Velasquez, et al., “Repeatability of 18F-FDG PET in aMulticenter Phase I Study of Patients with Advanced GastrointestinalMalignancies,” 50 J. Nucl. Med. (No. 10) 1646-1654 (October 2009). Inlocal practices and even in practices and research centers employingQuality Assurance checks, these issues with SUV calculations have leftoncologists and researchers needing to see significant changes in SUVvalues to be somewhat assured they are making sound treatment decisionsor reaching proper research conclusions.

While using SUVs comparisons from PET/CT static images are currently themost advanced way in clinical practices to assess tumor response totreatment, the use of dynamic images (PET images taken at various timesduring the uptake of the radio-labeled tracers) has provided researcherswith kinetic information regarding the uptake of radio-labeled tracers.In the academic community, this kinetic information is proving to be aneven better method of assessing treatment and predicting patientoutcomes than using static SUVs. (See Lisa K. Dunnwald, “PET TumorMetabolism in Locally Advanced Breast Cancer Patients UndergoingNeoadjuvant Chemotherapy: Value of Static versus Kinetic Measures ofFluorodeoxyglucose Uptake,” Clin. Cancer Res. 2011; 17:2400-2409(published online first Mar. 1, 2011)). Unfortunately, this dynamic PETapproach takes approximately three times as long as a static PET/CT scanand thus would require several more PET scanners at each hospital; it isclinically and economically impractical for widespread adoption andclinical use. So while there have been great improvements in the pastfew decades regarding cancer treatment options, today's oncologists andresearchers continue to lack a timely, cost-effective, and fast way toevaluate the effectiveness of the treatments they deliver or theresearch they are conducting.

In light of the problems associated with current tumor measurement andprediction systems, it is an object of the present invention to providea way to identify improperly administered radio-labeled tracerinjections (infiltrations or extravasation), which negatively impacttumor uptake and PET results, and an easier, less costly, and moreefficient system and method for measuring and predicting the statusand/or changes in biological processes.

SUMMARY

Disclosed are systems for identifying improperly administeredradio-labeled tracer injections and for measuring radio-labeled traceruptake into a biological system in an easy, quick and relativelyinexpensive manner along with requiring less radio-labeled tracer andinflicting less discomfort on the patient. The system can also be usedto measure biological processes in laboratory animals with higherthrough put and less expense than can be accomplished today. Physiciansand researchers are better able to make proper treatment and researchdecisions in a cost effective and efficient manner. Although embodimentsof the system of the present invention described below relate to qualitycontrol checks for identifying improperly administered radio-labeledtracer injections and measuring and predicting changes in a tumor, forexample, embodiments of the system of the present invention can be usedto measure processes in nearly any biological system. For example, thesystem can be used for non-tumor brain scans, assessing inflammation,evaluating kidney function, etc.

Any number of embodiments of the present invention provide a hardwareand software system which provides an indication of success in theadministration of radio-labeled tracer injections and is used to gatherreal-time measurements of radio-labeled tracer uptake in a biologicalprocess, for example a tumor. Sensors measure the localized uptake of aradio-labeled tracer which is injected into the patient or subject. Inan embodiment, for example, sensors can be placed in the followinglocations: (a) directly over the tumor; (b) on the upper right arm,approximately 10 cm above the antecubital fossa; (c) on the upper leftarm, approximately 10 cm above the antecubital fossa; and (d) overanother area of interest. By placing a sensor on the upper arm, abovethe injection site of the radiotracer, the device can assess whether ornot a relatively common complication in radiotracer injection hasoccurred. Properly administered injections of radio-labeled radiotracerspass underneath the injection arm sensor within several seconds of theinjection; infiltrations or extravasations remain in the arm tissueoutside the vascular system and are detected by the arm sensor.

In any number of embodiments, measurements taken at the sensors can beperformed quickly and repeated often. The system of the presentinvention reduces the amount of expensive radioactive tracer necessaryfor accurate measurement readings verse the amount required for othermeasurement methods and eliminates the necessity of using a large PETscanner or similar piece of equipment for follow-up scans (PET/CTscanners may continue to be used to stage diagnosed cancers and to checkthe subject for metastasis). Measurements made by the present approachreveal the kinetics of the tumor. Biological differences in tumors causedifferent amounts of radioactive analyte to be consumed locally ascompared to normal tissue. The present invention senses and quantifiesthis consumption, then processes the data into an easy-to-read graph forthe oncologist within minutes. Comparing graphs over time—baselineversus subsequent scans—shows the changes in tumor parameters. Changesin biological parameters within the tumor can give the physician insightinto whether treatment is working or not. Additionally, the presentinvention can use predictive algorithms to predict likely changes inbiological parameters based on one measurement scan, which speeds thetime required to know the likely effectiveness of treatment.

In any number of embodiments, the system can comprise: (i) one or moreMeasurement Sensors; (ii) a Measurement Control Device; (iii) ComputerSoftware capable of executing measurement and prediction data; and (iv)Database Server Control Software.

In one embodiment, a Measurement Sensor can be a device comprising ascintillation material; a light detector; and an embedded processor withassociated embedded software, memory, logic and other circuitry on aprinted circuit board. In an embodiment, for example, the sensor'selectronics are enclosed in a light-proof enclosure and there can be amulti-conductor cable to enable data communications. Mechanical designof the housing can be used to accurately control the placement of thescintillation material.

In one embodiment, a measurement control device can be, for example, adevice comprising a display screen, a keypad and data communicationsconnectors. The control device can further comprise an embeddedprocessor with associated embedded software, memory, a real-time clock,and other associated logic and circuitry on a printed circuit board. Inan embodiment, there can be multiple data communications connectors toenable the attachment of multiple measurement sensors. Anotherembodiment of the control device also includes a data communicationsconnector to enable connection to a computer.

In any number of embodiments, the specialized computer software used inthe system of the present invention is capable of: (1) performingdiagnostic tests on the measurement control device; (2) transferringmeasurement data from the measurement control device and saving it to arecord file; (3) gathering ancillary test data from the user or othersources (radiation dose administered, patient weight, patientblood-glucose readings, PET scan data, etc.) and including it in thedata record file; and (4) transferring the data record file to thedatabase server control software.

In any number of embodiments, the database server control software canbe capable of accepting incoming data record files from the computersoftware and applying one or more Algorithms to the data received.Simple algorithms include, but are not limited to smoothing and/or noisereduction, radioactive decay correction, amplitude correction based oncontrol signals, etc. More complex algorithms can be machine learningalgorithms such as Classification Decision Trees, Rule Learning,Inductive Logic, Bayesian Networks, etc. Measurement data can be storedin a central database while the Algorithm output can be used to generatereports for the user. These reports can indicate estimated parameters oreven estimated future parameters of a tumor or other biological process.

Some system embodiments may be directed to the ex vivo real-timedetection of gamma radiation emitted by a subject from administrationand uptake over a period of time of a radioactive analyte that decays invivo by positron emission. These systems may include at least one exvivo gamma radiation measurement sensor to detect gamma radiation over adesired period of time and to produce signal data associated with thedesired period of time, the ex vivo measurement sensor adapted tosensing gamma radiation proximate to a point of administration on thesubject of the radioactive analyte. These systems may also include atleast one computer processor having a non-transient memory and a clock,the computer processor in operable communication with the measurementsensor, a temperature compensator, and computer program code. Thesesystems may also include a signal amplifier in operable communicationwith the gamma radiation sensor where the signal amplifier is adapted toamplify the signal data and includes at least one sensor output for suchamplified signal data.

An ex vivo measurement sensor may have a sensor housing, a scintillationmaterial, a light detector, a temperature sensor, a signal amplifier,and a sensor power source. The light detector, temperature sensor,signal amplifier, and sensor power source may generally be in operablecommunication. The scintillation material and light detector may bedisposed within the sensor housing in a light proof manner, with thescintillation material adapted to receive a level of gamma radiationover the period of time from the in vivo radioactive analyte and to emitphotons representative of the gamma radiation level. The light detectormay be disposed with respect to the scintillation material so as toreceive and convert the photons into signal data representative of thefrequency level over time of gamma radiation received. The signalamplifier may be adapted to amplify the signal data, the measurementsensor having at least one sensor output for such amplified signal data.

The at least one computer processor may include a non-transient memoryand a clock, with the computer processor being in operable communicationwith the measurement sensor. The memory may have control computerprogram code executable by the at least one computer processor. Thecontrol computer program code may include a number of software modules,such as a first module for measurement, a second module for datamanagement (with “module” intended to simply mean portion of softwareprogram code directed to the function).

A temperature compensator may be coupled with the temperature sensor,such that the temperature sensor is adapted to measure an ambienttemperature. The system may thus communicate the ambient temperature tothe temperature compensator, so that the temperature compensatorgenerates a temperature correction factor based on comparison of theambient temperature to a reference temperature. The temperaturecompensator may be further adapted to apply the temperature correctionfactor to the signal data to produce temperature compensated signaldata.

The first module may be adapted to receive the signal data in a recordfile format, and the second module may be adapted to receive the signaldata of a record file from the first module and to transmit thecompensated signal data to a desired storage. The computer program codemay further include a third module adapted to receive stored data of arecord file from the second module, and to apply such stored data tocalculate changes in the compensated signal data over a desired period.This module may also apply stored data to a predictive model to generatepredictive data values over a desired period for such record file as apredictive outcome, and to transmit such changes to a desired storage.

Optionally, the ex vivo measurement sensor may include a radiationshielding mask for gamma radiation. The shielding mask may define anaperture in the form of a collimator for gamma radiation incident intothe scintillation material. An alignment feature or device may beincluded for removable alignment of the measurement sensor with respectto the subject. In some cases, the alignment feature may include a lightemitter disposed within the sensor so as permit alignment of thecollimator aperture to a desired portion of the subject by illuminationof the subject. Optionally, the light emitter may be a light emittingdiode (LED) disposed within the aperture, and optionally the ex vivomeasurement sensor may further include light proof sealant about the LEDto prevent the light from the output of the diode (or ambient light) tostrike the scintillation material, while permitting the scintillationmaterial to receive incident gamma radiation.

Optionally, the ex vivo measurement sensor may further include aradiation shielding mask for gamma radiation, with the shielding maskdefining an aperture in the form of a collimator for gamma radiationincident into the scintillation material; and the system further mayinclude a stand alignment device or feature for the removable mountingof the ex vivo measurement sensor in a configuration relative to thesubject so as to permit alignment of the collimator aperture to adesired portion of the subject.

Optionally, the third module may detect infiltration conditions. In oneapproach, the third module may calculate changes in the compensatedsignal data in order to determine infiltration of radioactive analyte.In another approach, the predictive model may include datarepresentative of radiation frequency over time associated withinfiltration of the analyte within the subject for determining aninfiltration. Such a predictive model may include data representative ofspike of radiation frequency over time associated with administration ofthe analyte for determining proper administration of the analyte. Analarm or indicator may be included to announce the determination ofinfiltration. Also optionally, some embodiments may include an arm-bandfor removable affixation of the ex vivo measurement sensor to an arm ofthe subject.

Optionally, a noise reduction filter may be included for filtering theamplified signal data based on amplitude or pulse height. Such a filtermay be implemented with a voltage comparator. Alternatively, the filtermay comprises an analog to digital converter and control computerprogram code adapted to compare digital amplified signal data to areference level.

A further system embodiment may also be directed to the ex vivoreal-time detection of gamma radiation emitted at an area of interest bya subject from administration and uptake over a period of time of aradioactive analyte that decays in vivo by positron emission. Such anembodiment may include a primary ex vivo measurement sensor and asecondary ex vivo measurement sensor. The primary ex vivo measurementsensor may include a sensor housing with a radiation shield, the sensorhousing with the radiation shield defining a cavity, the radiationshield further defining an aperture into the cavity, a collimatordisposed within the aperture so as to admit a collimated gamma radiationinto the cavity from the area of interest, a scintillation materialdisposed within the cavity such that the collimated gamma radiation isincident on the scintillation material, a light detector disposed withinthe sensor housing to detect light emitted from the scintillationmaterial, a temperature sensor, a signal amplifier, and a sensor powersource. The light detector, temperature sensor, signal amplifier, andsensor power source in operable communication.

In general, the scintillation material and light detector may bedisposed within the sensor housing with the scintillation materialadapted to receive a level of gamma radiation over the period of timefrom the in vivo radioactive analyte, and to emit photons representativeof the gamma radiation level. As above, the light detector disposed withrespect to the scintillation material is adapted to receive and convertthe multiplied photons into signal data representative of the frequencylevel over time of gamma radiation received. The signal amplifier mayamplify the signal data, and the measurement sensor may have at leastone sensor output or port for such amplified signal data.

In this embodiment, the secondary ex vivo measurement sensor may beunshielded for measuring background gamma radiation. In addition, acollimator alignment system may be provided in operable engagement withthe sensor housing for aligning the collimator to the area of interest.

A temperature compensator may be coupled with the temperature sensor,such that the temperature sensor is adapted to measure an ambienttemperature. The system may thus be adapted to communicate the ambienttemperature to the temperature compensator, so that the temperaturecompensator generates a temperature correction factor based oncomparison of the ambient temperature to a reference temperature. Thetemperature compensator may be further adapted to apply the temperaturecorrection factor to the signal data to produce temperature compensatedsignal data.

The at least one computer processor includes a non-transient memory anda clock, with the computer processor in operable communication with theprimary and secondary measurement sensors. The memory may have or storecontrol computer program code executable by the at least one computerprocessor, the control computer program code may have a first module formeasurement and a second module for data management. The first modulemay be adapted to receive the signal data in a record file format. Thesecond module is adapted to receive the signal data of a record filefrom the first module and to transmit the compensated signal data to adesired storage. Also included may be third and fourth modules ofcomputer program code, the third module adapted to receive stored dataof a record file from the second module, (i) to apply such stored datato a predictive model to generate predictive data values over a desiredperiod for such record file as a predictive outcome, and to transmitsuch predictive outcome to a desired storage; and (ii) to apply suchstored data to calculate changes in the compensated signal data over adesired period, and to transmit such changes to a desired storage andthe fourth module adapted to subtract signal data from the secondary exvivo measurement sensor from signal data from the primary ex vivomeasurement sensor.

This embodiment may include options corresponding to the options of theforegoing embodiment, though as appropriate for the primary ex vivomeasurement sensor.

A further system embodiment for the ex vivo real-time detection over aperiod of time of gamma radiation emitted by a subject from theadministration of a radioactive analyte that decays in vivo may includeat least one ex vivo gamma radiation measurement sensor to detect gammaradiation over a desired period of time and to produce signal dataassociated with the desired period of time, the ex vivo measurementsensor adapted to sensing gamma radiation proximate to a point ofadministration on the subject of the radioactive analyte. The system mayalso include a signal amplifier in operable communication with the gammaradiation sensor, the signal amplifier adapted to amplify the signaldata, the measurement sensor having at least one sensor output for suchamplified signal data. They system may also include at least onecomputer processor and a non-transient memory, the computer processor inoperable communication with the non-transient memory and the measurementsensor output port. In such systems, the non-transient memory mayinclude computer program code executable by the at least one computerprocessor, and the computer program code may be configured forperforming the steps of receiving the amplified signal data with thedesired period of time and one or more associated patient administrationfactors, accessing reference data distributed over a reference period oftime and one or more associated reference administration factors, andcomparing the amplified signal data and patient administration factorsto the reference data and reference administration factors to determinea likelihood of improper administration of the radioactive analyte tothe subject and administration factors associated with improperadministration.

In some embodiments, patient or reference administration factors mayinclude one or more of an identity of an individual administering theradioactive analyte, a method of administration of the radioactiveanalyte, a dose of radioactive analyte administered, a type ofradioactive analyte, a type of device used to administer radioactiveanalyte, an amount of time the device used to administer radioactiveanalyte is in place, a needle gauge used to administer the radioactiveanalyte, a flush volume used in conjunction with the administration ofthe radioactive analyte, a location of administration of the radioactiveanalyte, an orientation of administration of the radioactive analyte, apresence of an autoinjector, a type of patient therapy, and one or morepatient characteristics. In addition, the one or more patientcharacteristics may include patient weight, height, age, body-massindex, patient sex, patient hydration, patient movement after injection,blood pressure, and blood-glucose.

The system may be configured to store administration factors determinedto be associated with a likelihood of improper administrations above athreshold, and/or alert to a user when one or more administrationfactors associated with improper administrations above the threshold arepresent. The likelihood of improper administration may also be storedwith a diagnostic image (e.g., from a PET scan) associated with theadministration of a radioactive analyte for reference by a userinterpreting the diagnostic image. In some embodiments, the system mayalso determine one or more administration factors associated with alikelihood of improper administration below a threshold.

A further method for the ex vivo real-time detection over a period oftime of gamma radiation emitted by a patient from the administration ofa radioactive analyte that decays in vivo may include the steps ofidentifying one or more patient administration factors associated withthe administration of a radioactive analyte, applying at least one exvivo gamma radiation measurement sensor proximate to a point ofadministration on the subject of the radioactive analyte, detectinggamma radiation over a desired period of time and producing signal dataassociated with the desired period of time, amplifying the signal datausing a signal amplifier in operable communication with the gammaradiation sensor, wherein the measurement sensor includes at least onesensor output for such amplified signal data and outputting theamplified signal data, and processing the amplified signal data using acomputer processor in operative communication with a non-transientmemory and the measurement sensor output. In some embodiments, theprocessing may include the steps of receiving the patient administrationfactors and amplified signal data associated with the desired period oftime, from the non-transient memory, accessing reference administrationfactors and reference data distributed over a reference period of time,and comparing the amplified signal data and patient administrationfactors to the reference data and reference administration factors todetermine a likelihood of improper administration of the radioactiveanalyte to the subject and administration factors associated withimproper administration.

In some embodiments, the patient or reference administration factors mayinclude an identity of an individual administering the radioactiveanalyte, a method of administration of the radioactive analyte, a doseof radioactive analyte administered, a type of radioactive analyte, atype of device used to administer radioactive analyte, an amount of timethe device used to administer radioactive analyte is in place, a needlegauge used to administer the radioactive analyte, a flush volume used inconjunction with the administration of the radioactive analyte, alocation of administration of the radioactive analyte, an orientation ofadministration of the radioactive analyte, a presence of anautoinjector, a type of patient therapy, and one or more patientcharacteristics. The patient characteristics may include patient weight,height, age, body-mass index, patient sex, patient hydration, patientmovement after injection, blood pressure, and blood-glucose.

The exemplary method may also include the step of storing administrationfactors determined to be associated with a likelihood of improperadministrations above a threshold, and/or alerting a user to thepresence of one or more administration factors associated with improperadministrations above the threshold. The method may also include thestep of storing the likelihood of improper administration with adiagnostic image associated with the administration of a radioactiveanalyte for reference by a user interpreting the diagnostic image. Themethod may also include the step of determining administration factorsassociated with a likelihood of improper administration below athreshold.

One method for identifying patient administration factors associatedwith an improper administration of radioactive analyte to a set ofpatients may include the step of identifying and collecting a set ofpatient administration factors associated with the administration of aradioactive analyte to each patient in the set of patients, anddetermining, for each patient, whether the radioactive analyte wasadministered properly in accordance with methods disclosed herein. Themethod may also include the step of identifying one or more patientadministration risk factors, wherein patient administration risk factorscomprise patient administration factors that correlate withadministrations where the likelihood of improper administration is abovea threshold. The patient administration factors and patientcharacteristics may include those factors and characteristics disclosedherein.

The method may also include the step of reporting the one or morepatient administration risk factors to a user, and/or mitigating againstthe one or more patient administration risk factors in future patientadministrations. The method may also include the step of identifying oneor more patient administration factors that correlate withadministrations where the likelihood of improper administration is belowa threshold.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of an overview of the system.

FIG. 2 is a schematic of a measurement sensor of an embodiment of thesystem.

FIG. 3 is shows an embodiment of a measurement sensor of the system.

FIGS. 4A-4C illustrate optional aspects of the system.

FIGS. 5A-5C illustrate embodiments of measurement control devices.

FIG. 6 illustrates an embodiment of computer program code of the system.

FIG. 7 shows an embodiment of a printed circuit board and light shield.

FIGS. 8A-8B illustrate an embodiment of a light shield.

FIG. 9 shows an aspect of embodiments of the system.

FIGS. 10A-10B show embodiments of a measurement sensor.

FIG. 11 is a diagram illustrating locations on a subject's body wheresensors may be placed.

FIG. 12 is a flow diagram of an embodiment of components the system.

FIG. 13 is a schematic diagram illustrating aspects of an embodiment ofthe system.

FIG. 14 is a schematic of an embodiment of a measurement sensor.

FIG. 15 is a schematic diagram illustrating aspects of an embodiment ofa measurement sensor.

FIG. 16 is a detailed exploded view of an embodiment of a measurementsensor.

FIG. 17 is a flow diagram illustrating an embodiment of measurementsensor operation.

FIG. 18 a schematic diagram illustrating aspects of an embodiment of ameasurement control device.

FIG. 19 is a front prospective view of an embodiment of a measurementcontrol device.

FIG. 20 is a front prospective view of an embodiment of a measurementcontrol device with measurement sensors attached.

FIG. 21 is a flow diagram illustrating measurement control deviceoperation in an embodiment.

FIG. 22 is a flow diagram illustrating computer software operation in anembodiment.

FIG. 23 is a flow diagram illustrating database controller softwareoperation in an embodiment of the system.

FIG. 24-26 show the output from an injection arm sensor fromadministration or injection of a radioactive analyte, with FIG. 24 aproper administration and FIGS. 25 & 26 showing improperly administeredradioactive analyte.

FIGS. 27 and 28 shows an embodiment of a combined measurement sensor andmeasurement controller, along with an embodiment of an arm band.

FIG. 29 shows an embodiment of a light shield.

FIG. 30 shows an exploded view of an embodiment of a light shield andthe internal components that are being shielded from light.

FIG. 31 shows an embodiment of a light shield combined with an alignmentlight source.

FIG. 32 shows a cut-away view of an embodiment of a light shieldcombined with an alignment light source.

FIG. 33 shows an exploded view of an embodiment of a light shieldcombined with an alignment light source.

FIG. 34 shows an embodiment of a measurement controller.

FIG. 35 shows an embodiment of two daisy chained measurementcontrollers.

FIGS. 36 and 37 show embodiments of a measurement sensor.

FIG. 38 shows an exploded view of an embodiment of a light shield on anembodiment of a measurement sensor.

FIGS. 39 and 40 show a view of an embodiment of a radiation shieldingmask alignment device.

FIG. 41 shows an embodiment of a radiation shielding mask, while FIG. 42shows a top view of an embodiment of a radiation shielding mask.collimator.

FIG. 43 shows a bottom view of an embodiment of a radiation shieldingmask and collimator.

FIG. 44 shows an embodiment of a measurement sensor attached to anembodiment of a radiation shield.

FIG. 45 shows an embodiment of a radiation shield alignment device andan embodiment of a radiation shield.

FIG. 46 shows a cut away view of an embodiment of a measurement sensorattached to an embodiment of a radiation shield.

FIG. 47 shows a cut away view of an embodiment of a measurement sensorattached to an embodiment of a radiation shield.

FIG. 48 shows a cut away view of an embodiment of a radiation shieldalignment device attached to an embodiment of a radiation shield.

FIG. 49 shows an embodiment of a measurement sensor and attachedradiation shield attached to a measurement sensor stand.

FIG. 50 shows a detailed view of an embodiment of a measurement sensor

FIG. 51 shows an embodiment of a measurement sensor attached to anembodiment of a radiation shielding mask with adjustment legs.

FIG. 52 shows an embodiment of a measurement sensor attached to anembodiment of a radiation shielding mask with adjustment legs.

FIGS. 53 and 54 show embodiments of measurement sensors daisy chainedtogether.

FIG. 55 shows three embodiments of measurement sensors.

FIG. 56 shows an embodiment of a measurement sensor with attachedexternal push button.

FIG. 57 shows a cut away view of an embodiment of a measurement sensorwith backscatter material.

FIG. 58 shows an embodiment of a measurement sensor housing withintegrated locating structure for a backscatter material.

FIG. 59 is a method implementation of the present approach.

DETAILED DESCRIPTION

Disclosed is a system for measuring gamma radiation emitted from anin-vivo administered radioactive analyte. If repeated measurements aremade, these measurements will show changes in the measured radiationover time. These repeated measurements can be used to calculateparameters related to the data. The repeated measurements can also beused as inputs to predictive algorithms to predict future parameters.

The system is a hardware and software system which can be used to gatherreal-time or dynamic measurements of radio-labeled tracer uptake in abiological process, for example a tumor, muscle, or other tissue. Itemploys a sensor for the detection of gamma radiation emitted by asubject from a systemic or local administration of a radioactive analytethat generally decays in vivo by positron emission. A sensor for gammaray detection enables the use of ex vivo or in-vivo devices, whileex-vivo devices can be safer for the subject due to their less intrusivedesign. Elements and capabilities of embodiments of the system aredescribed in more detail below.

The system 10 employs a scintillation material 20 that converts gammaradiation to visible light. A light detector 21 then converts thevisible light to an electrical signal. This signal is amplified and isprocessed to measure the captured radiation. In ex vivo embodiments,temperature of the sensor is recorded along with this radiationmeasurement, and this data may be collected by a measurement controlleror control device 12 into a record file 80. This record file 80, alongwith others like it from previous measurement sessions, may be used asinputs to calculate data parameters or as input to predictive models topredict data parameters. Record file 80 is intended simply to denote acollection of data by subject 5, and such other criteria applicable tothe circumstances, such as tumor location, condition, time of test, etc.

An embodiment of system 10 shown in FIG. 1 is directed to the detectionof gamma radiation emitted by a subject 5 (not shown) from systemicadministration of a radioactive analyte that decays in vivo by positronemission. The system 10 may include one or more measurement sensors 11(or device for the detection of radiation), a measurement control device12, an optional processing station 70, and optional database 75.Communication links 7 may be wired or wireless, depending on theapplication, and may extend data reporting or other communication tonetworks or the internet 77. The system 10 may include a visible,audible, or other means of indicating the status of the radioactiveanalyte injection, including the likelihood of injection infiltration.

With reference to FIG. 2 , measurement sensor 11 may have a sensorhousing 25 (not shown), a scintillation material 20, a light detector21, a temperature sensor 36, a signal amplifier 33, a sensor processor22, a non-transient sensor memory 30, and a sensor power supply 32.Light detector 21, temperature sensor 36, signal amplifier 33, sensorprocessor 22, sensor memory 30, and sensor power supply 32 may be inoperable communication, whether by wiring, circuit board tracing, etc.

As shown in the exploded illustration of FIG. 3 , scintillation material20 and light detector 21 may be disposed or located within housing 25for use, depending on the application. Sensor housing 25 may befabricated of metal (e.g., nickel, copper, brass, bronze, steel,aluminum, nickel-silver, beryllium-copper, etc.) or plastic (PE, PP, PS,PVC, ABS, etc.), Such sensor housing 25 may optionally be light proof,so as to protect scintillation material 20 and light detector 21 fromambient or surrounding light. Optionally, sensor housing 25 may definean outer surface and comprises a light-proof coating on the outersurface. Sensor housing 25 may also protect such internal componentsfrom environmental degradation, such as the exposure of scintillationmaterial 20 to elevated humidity. Sensor housing 25 may include orincorporate a shielding mask 38 or shield for the radiation of concern,such as the ex vivo detection of gamma radiation. Shielding mask 38 maybe fabricated from materials such as iridium, platinum, tungsten, gold,palladium, lead, silver, molybdenum, copper, nickel, bronze, brass,iron, steel, zinc, titanium, and aluminum. As shown in FIGS. 57 and 58 ,any number of embodiments the sensor housing 25 could include astructure for placement and alignment of a backscatter material 82.

In use, and as shown in FIGS. 4A-C, embodiments of sensor housing 25 mayinclude an adhesive 25A adapted for the removable attachment of thehousing to the skin of the subject 5. Optionally, system 10 may includea measurement sensor carrier 35 adapted to removably engage with themeasurement sensor 11. The measurement sensor carrier 35 may define acarrier surface with a portion of which may comprise an adhesive 35Aadapted for removable attachment of the measurement sensor carrier 35 tothe skin of a subject 5 (not shown). Optionally, measurement sensorcarrier 35 includes or defines one or more alignment features 35F thatpermit the repeated alignment of the measurement sensor carrier 35 tothe subject. For example in the embodiment as shown, measurement sensorcarrier 35 defines two features 35F that could be used to align a markerto make a mark or stain dot on the skin of subject 5. For a repeatedtrial, measurement sensor carrier 35 might be placed in a position sothat alignment features 35F might align with the marks on the skin ofsubject 5, ensuring that measurement sensor 11 is in the properlocation. Measurement feature 35F may include a variety of approachesdepending on the application, such as pads for temporary tattoomarkings, peripheral outline ridges, guides permitting the marking oforientation axes, etc. Additionally, embodiments of sensor housing 25may include a means of attachment to an arm band 78 for attachment tothe arm of subject 5. This arm band may include hook and loop fasteners79 or other means of securing to subject 5. An embodiment may include apocket or other means of securing the sensor 11 with respect to the armband.

Sensor power supply 32, or the other power supplies discussed herein,may be a battery, a hardwire power connection, transformer, or some formor source of power generation. In some embodiments, sensor power supply32 in particular, may be a microelectromechanical machine adapted togenerate electricity from subject 5, possibly employing the motion ofsubject 5, or blood pressure, etc.

Scintillation material 20 may be placed within a gamma radiation flux,with scintillation material 20 being adapted to receive a level of gammaradiation from the in vivo radioactive analyte and to emit photonsrepresentative of or corresponding to the gamma radiation level. Lightdetector 21 may be juxtaposed, located, or generally disposed withrespect to the scintillation material 20 so as to be adapted to receiveand convert the multiplied photons into signal data representative ofthe level of gamma radiation received. It is contemplated that someapplications may include mechanisms or structure for directing lightfrom scintillation material 20 to light detector 21, such as fiberoptics, prisms, reflectors, etc. Optionally, and as shown in FIG. 3 ,light detector 21 may have an active area 21A sensitive or receptive tolight as described herein, and the scintillation material 20 may beconfigured and sized to substantially match the active area, which mayimprove efficiency and reduce the effect of stray light or backgroundsignals.

The scintillation material 20 may be selected for or adapted to theradiation detection application. In some embodiments for gammaradiation, scintillation material 20 may be selected from a groupconsisting of bismuth germanate, gadolinium oxyorthosilicate,cerium-doped lutetium oxyorthosilicate, cerium-doped yttriumoxyorthosilicate, sodium iodide, thallium-doped sodium iodide,polyvinyltoluene, and cadmium zinc telluride.

Measurement sensors 11 may include a signal amplifier 33 that is adaptedto amplify the signal data, a sensor memory 30 including a measurementsensor identifier 16 (FIG. 6 ), and at least one sensor output port 27for communication or output of the amplified signal data. Depending onthe mode of communication desired, sensor output port 27 may be any of avariety of ports, such as electrical jack, computer communication (e.g.,CAT-5), optical, infrared, radio transmitter, etc.

In reference to the examples in FIGS. 5A-C, the system 10 may include acontroller or measurement control device 12 having a control processor42, a non-transient control memory 40, a control power supply 52, and aclock 48, all in operable communication, whether by wiring, circuitboard tracing, etc. The measurement control device 12 may include acontrol input port 47 operably engaged with the sensor output port 27(not shown) and adapted to receive amplified signal data from themeasurement sensor 11. Operable engagement may include wired or wirelesscommunication, in any of a variety of communication protocols. Forexample, control input port 47 may be operably engaged with the sensoroutput port 27 by cable (e.g., multiconductor cable 24), circuit boardtracing, or by wireless communication. In addition to amplified signaldata, it may be desirable to communicate other data or information frommeasurement sensor 11 to measurement control device 12, such asoperating parameters, power storage, equipment status, or other sensordata. Optionally, measurement control device 12 may include a display 44and data entry device 45, such as a touch screen, or other input/outputstructure. Embodiments may include a controller or measurement controldevice 12 and one or more sensors 11 contained within the same housing,and operably engaged.

The control memory 40 may, among other things, include control computerprogram code 56 (FIG. 6 ) executable by the control processor 42.Control computer program code 56, for example, may include a firstmodule 61 for implementing measurement functions and a second module 62for data management. For example, the first module 61 may be adapted toreceive a previously assigned measurement sensor identifier 16(discussed below), the signal data, and a subject identifier and toassociate the signal data, sensor identifier, and measurement sensoridentifier 16 in a record file 80 format. The second module 62 may beadapted to receive the signal data of a record file 80 from the firstmodule 61 and to transmit the compensated signal data to a desiredstorage. Such storage may be local memory (e.g., sensor or control),external memory, a remote computer memory, networked memory (wireless orwired), or memory accessed via the internet.

The system 10 may include a temperature compensator 50 coupled with thetemperature sensor 36, the temperature sensor 36 adapted to measure anambient temperature within the system 10 adapted to communicate theambient temperature to the temperature compensator 50. In this way, thetemperature compensator 50 may be adapted to generate a temperaturecorrection factor based on comparison of the ambient temperature to areference temperature. As discussed below, components within measurementsensor 11 may be temperature sensitive. The temperature compensator 50may also be adapted to apply the temperature correction factor to thesignal data to produce temperature compensated signal data. Temperaturecompensation may not be required for embodiments directed to in vivosensing. Additionally, some embodiments of the system 10 may include ameans of temperature response calibration which would nullify the impactof temperature on the operation of system 10. This nullification couldbe accomplished by measuring the response a sensor 11 has with respectto temperature, and then modifying the parameters of amplifier 33 orother circuit components so as to counteract this temperature response.

Optionally, as shown in FIGS. 7-8 , and FIGS. 29-33 , embodiments ofmeasurement sensor 11 may include an internal disposed light shield 28.Such an embodiment may include a printed circuit board assembly 23Phaving a board 23 defining a plane with a first surface 23A and anopposing second surface 23B. Light shield 28 may be adapted for mountingonto the first surface 23A of the board 23, thereby shielding thescintillation material 20 and light detector 21 from ambient light. Thescintillation material 20 and light detector 21 may be ensconced in orsurrounded by light shield 28. For example, given that the scintillationmaterial 20 has a first width parallel with the plane and the lightdetector 21 has a second width parallel with the plane, then lightshield 28 may define a first cavity 28A with a third width equal orgreater than the first width such that the first cavity 28A is adaptedto receive the scintillation material 20, and the light shield 28 mayalso define a second cavity 28B with a fourth width equal or greaterthan the second width such that the second cavity 28B is adapted toreceive the light detector 21. First and second cavities 28A, 28B may bein communication and in such proximal relation that the light shield 28optically aligns the scintillation material 20 to the light detector 21when the scintillation material 20 is received by the first cavity 28Aand the light detector 21 is received by the second cavity 28B. Thesecomponents may be operably engaged with the printed circuit boardassembly 23P when mounted. For purposes herein, the term “width” isintended to connote an effective width that permits the nestingdescribed, and not any particular required cross sectional shape. Inother words, the term “width” is intended to permit the reception of thecomponents as described, and not to limit cross section shape of thosecomponents beyond their interrelation. In an embodiment of the lightshield 28, a light proof sealant 81 may be used to seal the cavitiesafter assembly of the scintillation material 20 and light detector 21.This light proof sealant 81 may, for example, be an epoxy, caulk,potting compound, etc.

Such a light shield 28 may be made from materials selected from a groupof metals (e.g., copper, brass, bronze, steel, aluminum, nickel-silver,beryllium copper, silver, gold, nickel), or plastic (e.g., ABS, Acetal,Acrylic, Fluoroplastic, Polycarbonate, Nylon, PVC, Polypropylene,Polystyrene, Polyethylene ABS, Acetal, Acrylic, Fluoroplastic,Polycarbonate, Nylon, PVC, Polypropylene, Polystyrene, Polyethylene).Optionally, the light shield 28 may be made from one material and platedor coated in another, to enhance its ability to be soldered or mountedon printed circuit board assembly 23P.

If made from metal or metal clad or plated plastic, the light shield 28may be fixed into place on printed circuit board assembly 23P as asurface-mount-component using either leaded or lead-free solder, or as athrough-hole-component using portions of the light shield 28 thatprotruded through holes in the circuit board, the holes then filled withsolder. If made from plastic, the light shield 28 may be fixed intoplace on the printed circuit board assembly 23P as a snap-on part withportions of the shield that protrude through holes in the printedcircuit board assembly 23P that spring into position and resistreversing out of the holes, as a swage-on part with portions of theshield that protrude through such holes and that are then melted orswaged to prevent them from reversing out of the holes. Additionally,light shield 28 may be mounted detached from the printed circuit board,incorporating wired connections thereto.

Optionally, light shield 28 may have one or more through-holes in it toallow pressure to equalize during assembly or to allow for out-gassingduring assembly. Such holes may then be covered, possibly withlight-proof foil tape or sealant 81, after assembly to complete thelight-proof nature of the shield.

As shown in FIG. 7 , light shield 28 may also enclose a light emitter 31(e.g., LED, light bulb, laser diode) such that the light emitter couldbe used to generate pulses of light within the enclosure of the lightshield 28 to test the light detector 21. Thus, system 10 may include alight emitter 31 in operable communication with the sensor power supply22, the light emitter 31 disposed within first or second cavity 28A, 28B(or other proximal cavity), such that the light shield 28 is adapted toreceive the light emitter 31 in a location that is proximal to the lightdetector 21.

In some embodiments, the control computer program code 56 furthercomprises a third module 63 adapted to receive stored data of a recordfile from the second module 62. The third module 63 may apply suchstored data to a predictive model to generate predictive data valuesover a desired period for such record file as a predictive outcome, andto transmit such predictive outcome to a desired storage. In otherembodiments, the third module 63 may to apply such stored data tocalculate changes in the compensated signal data over a desired period,and to transmit such changes to a desired storage. In other embodiments,the third module 63 may to apply such stored data to calculate changesin the compensated signal data from background data over a desiredperiod, and to transmit such changes to a desired storage. Suchbackground data may be drawn from a second measurement sensor 11, apreviously calculated background radiation level, or a separateradiation sensor, depending on the application. In other embodiments,the third module 63 may be adapted to apply such stored data tocalculate the quality of a radioactive analyte injection, such as tomonitor changes in compensated signal data or otherwise calculate thelikelihood of injection infiltration. A result of this may betransmitted to a display and/or a desired storage. This could alert orinform the user of the status, whether by visual, audible or otherindication means.

FIG. 24 shows the radiation pulse count amplitude or output over timefrom an injection arm sensor 11 with a properly administered radioactiveanalyte, with a low level prior to injection 88, an injection spike 89,and a low level post injection 90. This signal data forms a distinctiveparametric pattern (i.e., amplitude, slope, time), which ischaracteristic of the proper administration of a radioactive analyte.The injection spike 89, followed by the low level post injectiondemonstrates dispersal of the radioactive analyte after a properadministration or injection. FIG. 25 shows an output from an injectionarm sensor 11 with an improperly administered radioactive analyte (i.e.,infiltration or extravasation) in 91, as well as non-administration armlow levels 92, and illustrating the approximate extremely high level ofcounts or amplitude at the approximate time 93 at which a PET Scan mighttypically be taken. FIG. 26 shows an output from an injection arm sensor11 with another improperly administered radioactive analyte (i.e.,infiltration or extravasation) in 94, as well as non-administration armlow levels 95, and illustrating the approximate normal low level ofcounts or amplitude (obtained by extrapolating from availablemeasurements, as shown by the dashed lines) at the approximate time 96at which a PET Scan might typically be taken. The parametric patternsand data characteristic of improper administration can thus bedistinguished in comparison to the parametric pattern and data of properadministration. Without the present approach, the improperadministration would be impossible for clinicians to detect. In additionto infiltration or extravasation, improper administration may include orbe characterized by other inaccuracies in the desired dispersion ofradioactive analyte (e.g., protocol deviation).

In some embodiments, system 10 may include a processing station 70(FIGS. 1 & 9 ). Processing station 70 may be a computer in communicationwith measurement control device 12. Embodiments of processing station 70may include a station processor, a non-transient station memory, and astation power supply; the station processor, station memory, and stationpower supply are in operable communication. The processing station 70may have a station input port operably engaged with the control outputport and adapted to receive data from the measurement control device 12.In some embodiments, the role of measurement control device 12 andstation 70 may be merged.

Similar to measurement control device 12, the processing station 70 mayinclude station computer program code 76 executable by the stationprocessor, the station computer program code including a third module 63adapted to receive stored data of a record file from the second module62, to apply such stored data to a predictive model to generatepredictive data values over a desired period for such record file as apredictive outcome.

Optionally, processing station 70 may include a docking device 71 forthe measurement control device 12. The docking device 71 may be inoperable communication with the station processor. Docking device 71could be adapted to receive the measurement control device in the formof a holder, retainer, charger, or cradle. When measurement controldevice 12 is docked, the docking device 71 may provide an electricalconnector that engages with measurement control device 12 for datacommunication and power exchange. In one embodiment, the third module 63may be adapted to calculate the quality of the radioactive analyteinjection, whether by identifying certain changes or modelling, such asto calculate the likelihood of injection infiltration. The stationcomputer program code could then transmit the result of this calculationto a desired storage. Additionally, the station computer program codecould alert the user of the calculation result using visual, audible orother indication means.

In some embodiments, a predictive model may be a classification machinelearning model. In other embodiments, predictive model may be anunsupervised cluster analysis. Such an unsupervised cluster analysis, orother predictive model, may be adapted to predicting future outcome,predicting an effect of tumor treatment, and predicting metastasis.

Some embodiments may involve multiple measurement sensors 11. Forexample, a system 10 may include a first and second measurement sensor11, the first measurement sensor 11 adapted to the detection of testgamma radiation emitted by a subject from systemic or localadministration of a radioactive analyte that decays in vivo by positronemission proximate to a test area. The second measurement sensor 11 maybe adapted to the detection of background gamma radiation emitted by asubject from systemic or local administration of a radioactive analytethat decays in vivo by positron emission proximate to a background area.Depending on the application, the control computer program code 56 orstation computer code 76 may further include a fourth module 64 adaptedto receive stored data of a record file from the second module 62including data from the first and second measurement sensors 11 and tosubtract signal data from the second measurement sensor 11 from signaldata from the first measurement sensor 11. In other applications, thefourth module 64 may be adapted to receive stored data of a record filefrom the second module 62 including data from the first and secondmeasurement sensors 11, and to subtract signal data from the secondmeasurement sensor 11 from signal data from the first measurement sensor11. Such embodiments may permit the subtraction of background radiationfrom sensor data. Additionally, such embodiments may permit theestimation of the likelihood that the system or local radioactiveanalyte injection resulted in infiltration.

In some embodiments, the signal data may be a plurality of pulses at apulse frequency over time. The first module 61 may be adapted tocommunicate a sampling frequency instruction to the sensor processor 22,the sampling frequency instruction being a function of the pulsefrequency of the signal data. In some embodiments, the first module 61is adapted to communicate an increasing sampling frequency instructionupon an increase in pulse frequency.

An aspect of present approach is a sensor or device for the detection ofradiation, the device comprising a measurement sensor 11 with a housing25, a scintillation material 20, a light detector 21, a light shield 28,a temperature sensor 36, a signal amplifier 33, a sensor processor 22, anon-transient sensor memory 30, and a sensor power supply 32. Lightdetector 21, temperature sensor 36, signal amplifier 33, sensorprocessor 22, sensor memory 30, and sensor power supply 32 may be inoperable communication by a printed circuit board assembly 23P. Printedcircuit board assembly 23P may have a board 23 defining a plane having afirst surface 23A and an opposing second surface 23B. Light shield 28may be adapted for mounting onto the first surface 23A of the board 23,thereby shielding the scintillation material 20 and light detector 21from ambient light. The scintillation material 20 and light detector 21may be ensconced in or surrounded by light shield 28. For example, giventhat the scintillation material 20 has a first width parallel with theplane and the light detector 21 has a second width parallel with theplane, then light shield 28 may define a first cavity 28A with a thirdwidth equal or greater than the first width such that the first cavityis adapted to receive the scintillation material 20, and the lightshield 28 may also define a second cavity 28B with a fourth width equalor greater than the second width such that the second cavity 28B isadapted to receive the light detector 21. First and second cavities 28A,28B may be in communication and in such proximal relation that the lightshield 28 optically aligns the scintillation material 20 to the lightdetector 21 when the scintillation material 20 is received by the firstcavity 28A and the light detector 21 is received by the second cavity28B. These components may be operably engaged with the printed circuitboard assembly 23P when mounted.

The scintillation material 20 and light detector 21 are thus disposedwithin the light shield 28 with the scintillation material 20 adapted toreceive a level of gamma radiation and to emit photons representative ofthe gamma radiation level. Light detector 21 is disposed with respect tothe scintillation material 20 so as to be adapted to receive and convertthe multiplied photons into signal data representative of the level ofradiation received.

As above, the signal amplifier 33 may be adapted to amplify the signaldata, the sensor memory 30 including a measurement sensor identifier,the measurement sensor 11 having at least one sensor output port 27 forsuch amplified signal data. Optionally, the light shield 28 may bemounted to the first surface 23A of the board with solder. In someembodiments, light shield 28 is selected from a group consisting ofmetal: copper, brass, bronze, steel, aluminum, nickel-silver, berylliumcopper, silver, gold, and nickel.

An aspect of some embodiments of system 10 for the detection of gammaradiation emitted by a subject is that at least one measurement sensor11 may have a hermetically sealed sensor housing 25 of biocompatiblematerial, a scintillation material 20, a light detector 21, a signalamplifier 33, a sensor processor 22, a non-transient sensor memory 30,and a sensor power supply 32, as shown in FIGS. 10A-10B. Light detector21, signal amplifier 33, sensor processor 22, sensor memory 30, andsensor power supply 32 may be in operable communication, whether bydirect wiring, circuit board tracing, wireless interaction, etc.Optionally, sensor housing 25 biocompatible material may be selectedfrom a group consisting of glass, polyether ether ketone, andultra-high-molecular-weight polyethylene appropriate for theapplication, such as meeting implantable standards for in vivoapplications, for example. As a further option, sensor housing 25 maycomprise an anchor 25F for securing an in vivo application in a desiredlocation for testing or sensing.

Similar to as discussed above with reference to FIG. 3 , light detector21 may have an active area 21A and the scintillation material 20 may beconfigured to substantially match the active area 21A. The scintillationmaterial 20 and light detector 21 may be disposed within the sensorhousing 25 with the scintillation material 20 adapted to receive a levelof gamma radiation from the in vivo radioactive analyte and to emitphotons representative of the gamma radiation level, the light detector21 disposed with respect to the scintillation material 20 so as to beadapted to receive and convert the multiplied photons into signal datarepresentative of the level of gamma radiation received. The signalamplifier 33 may be adapted to amplify the signal data. The sensormemory 30 may include a measurement sensor identifier 16, themeasurement sensor 11 having at least one wireless sensor output port 27for such amplified signal data.

Such an embodiment of measurement sensor 11 may work with an ex vivomeasurement control device 12 having a control processor 42, anon-transient control memory 40, a control power supply 52, and a clock48. Similar to as discussed above with reference to FIG. 5A-C, thecontrol processor 42, control memory 40, control power supply 52, andclock 48 may be in operable communication, whether by direct wiring,circuit board tracing, or otherwise. The measurement control device 12may have a wireless control input port 47 operably engaged with thewireless sensor output port 27 and adapted to receive amplified signaldata from the measurement sensor 11.

The control memory 40 may include control computer program code orsoftware 56 executable by the control processor 42 (FIG. 6 ). Suchcontrol computer program code or software 56 may include a first module61 for measurement and a second module 62 for data management. The firstmodule 61 may be adapted to receive the measurement sensor identifier16, the amplified signal data, and a subject identifier and to associatethe signal data, sensor identifier 16, and measurement sensor identifierin a record file 80 format. The second module 62 may be adapted toreceive the amplified signal data of a record file 80 from the firstmodule 61 and to transmit the amplified signal data to a desiredstorage.

Optionally, the system 10 may include an in vivo measurement sensor 11with a sensor housing 25 that is substantially tubular, which defines asensor housing outer surface 25S and a sensor housing length 25L (FIG.10B). In some such embodiments, the wireless sensor output port 27 maycomprise an antenna running substantially along the length 25L of thesensor housing 25, along with supporting transmitters, etc.Substantially along the length simply means by general orientation oralong a substantial portion, but it need not extend for the full lengthor be a straight antenna. It is contemplated, for example, that oneembodiment of sensor output port 27 may comprise a coiled antennaoriented along a portion of length 25L, as shown in FIGS. 10A-10B. Theanchor 25F may comprise at least one raised ring about a portion of acircumference of the sensor housing 25, which may or may not encirclethe full circumference. The at least one raised ring or anchor 25F maydisposed on the outer surface 25S and having a height from the outersurface of about 0.1-3.0 mm to anchor sensor housing 25 in place. Otherembodiments of anchor 25F may include features such as adhesive, raisedridges, bumps, or eyelets, to minimize movement with respect to apatient or subject 5. Sensor housing 25 may also be provided in othergeneral shapes.

In such an embodiment, optionally computer program code or software 56(FIG. 6 ) may further comprise a third module 63 adapted to receivestored data of a record file 80 from the second module 62, to apply suchstored data to a predictive model to generate predictive data valuesover a desired period for such record file as a predictive outcome, andto transmit such predictive outcome to a desired storage. In anotheroption, control computer program code or software 56 may comprise athird module 63 adapted to receive stored data of a record file 80 fromthe second module 62, to apply such stored data to calculate changes inthe amplified signal data over a desired period, and to transmit suchchanges to a desired storage. In yet another option, control computerprogram code or software 56 may comprise a third module 63 that isadapted to receive stored data of a record file 80 from the secondmodule 62, to apply such stored data to calculate changes in theamplified signal data from background radiation data over a desiredperiod, and to transmit such changes to a desired storage. In someembodiments, this third module may be adapted to calculate the qualityof the radioactive analyte injection, such as to calculate thelikelihood of injection infiltration. The computer program code couldthen transmit the result of this calculation to a desired storage.Additionally, the computer program code could alert the user of thecalculation result using visual, audible or other indication means.

In one embodiment, the signal data comprises a plurality of pulses at apulse frequency over time, and wherein the first module 61 is adapted tocommunicate a sampling frequency instruction to the sensor processor 22,the sampling frequency instruction being a function of the pulsefrequency of the signal data. The first module 61 may be adapted tocommunicate an increasing sampling frequency instruction upon anincrease in pulse frequency.

Processes that could be used in the manufacture of the measurementsensors 11 or other components may include many that are common withinthe electronics assembly industry, along with the following specificprocesses. For an embodiment of the system 10 that includes a gammaradiation mask or shield 38, for example, this mask or shield 38 may beglued, molded, swaged, screwed or otherwise mechanically fixed into themeasurement sensor housing 25. Then, the mask or shield 38 may be usedas a mounting plate for the other measurement sensor 11 components,including electrical components and additional housing components tocreate a lightproof sensor housing 25. As shown in FIGS. 57 and 58 , inany number of embodiments the sensor housing 25 could include structurefor placement and alignment of a backscatter material 82.

In another embodiment, the measurement sensor 11 components may bearranged within the measurement sensor housing 25, and then an epoxy,silicone or other curable fluid could be applied surrounding thecomponents. This method would hold the optical components in alignmentwhile also surrounding them with a light proof material.

In another embodiment of the measurement sensor 11 that includes awireless output port 27 as an antenna, it may be embedded in thestructure of the measurement sensor housing 25. For example, antennawire may be arranged on a mold form, then molding plastic may be appliedaround the form thus encapsulating the wires. With this method, theantenna wires could be of numerous designs for the optimization ofantenna efficiency. Additionally, this method could allow for a ferritematerial to be placed within the antenna portion of the housing 25 tofurther optimize the antenna efficiency.

Additional aspects or optional embodiments are provided below. Thepresent system enables (but does not require) radiation sensitivesensors to be placed ex vivo, such as on or near a test subject's skin.These sensors may measure the localized uptake of a radio-labeled tracerwhich is injected into the subject 5. In an embodiment as shown in FIG.1 , measurement sensors 11 may be placed in one or more of the followinglocations of FIG. 11 , for example: (a) directly over the tumor 1; (b)on the upper right arm 2, approximately 10 cm above the antecubitalfossa; (c) on the upper left arm 3, approximately 10 cm above theantecubital fossa, and (d) over the liver 4, immediately below the ribsand directly below the nipple. As shown in FIG. 2 , for example, anembodiment of the system 10 may comprise: (i) one or more measurementsensors 11; (ii) a measurement control device 12; (iii) computersoftware or computer program code 13 capable of executing certainfunctions, such as measurement and generation of predictive data orassessment as to the likelihood of an injection infiltration. The system10 may also include a desired storage for data, etc., with appropriatedatabases, database management or server control software 14, etc.

As shown in FIGS. 14 through 16 , a measurement sensor 11 can be, forexample, a device comprising a scintillation material 20; a lightdetector 21; and a sensor processor 22 with associated non-transientsensor memory 30, logic or sensor software 26, and other circuitrysupporting these components in operable communication, optionally with aprinted circuit board 23P (FIG. 16 ). FIG. 17 , for example, illustratesa flow diagram of operation of an embodiment of an ex vivo measurementsensor 11. In operation, a subject 5 may receive a systemic or localadministration by injection of a radioactive substance (also referred toas a tracer). When this radioactive substance decays, it releases oremits positrons (also referred to as high energy particles). Themeasurement sensor 11 uses a scintillation material 20 to receive gammaradiation from positron emission decay and to convert the radiation intophotons, such as pulses of light, which may then be detected by thelight detector 21. The sensor processor 22 may enable measurement andcollection of the photons, such as the number of light pulses detectedover a given amount of time. For example, a large number of light pulsesdetected per unit of time may correspond to a large concentration ofradioactive material. As the radioactive material concentration changes,the light pulses detected per unit of time changes accordingly. Bygraphing the light pulses counted versus time of data collection, avisual representation of radioactive concentration over time may beproduced. This graph indicates how the radioactive concentration ischanging. Optionally, noise rejection 37 (FIG. 14 ) may comprise afilter for filtering amplified signal data based on the height oramplitude of such pulses. For example, noise rejection 37 may include avoltage comparator or an analog to digital converter with computerprogram code to compare the digital output to a reference level.

Any number of small embedded processors are adequate for use in themeasurement sensor 11, and sensor processor 22 may include a dedicatedasynchronous counter of suitable size, if need for the application andif an external one is not included in the additional circuitry. Thesensor processor 22 may be embedded in the measurement sensor, or anexternal sensor processor 22 may be provided as applicable. The sensorprocessor 22 may be specially configured to satisfy various embodimentsof the system 10, depending on the requirements of the application. AnFPGA or other programmable logic device, for example, may be well suitedto this system, possibly incorporating a microprocessor sub-systemwithin the FPGA design.

Possible scintillation materials 20 include, but are not limited to:Bismuth Germanate (BGO); Gadolinium Oxyorthosilicate (GSO); Cerium-dopedLutetium Oxyorthosilicate (LSO); Cerium-doped Lutetium YttriumOrthosilicate (LYSO); Thallium-doped Sodium Iodide (NaI(T1)); PlasticScintillator (Polyvinyltoluene); or Cadmium Zinc Telluride (CZT). In anembodiment of a measurement sensor 11, multiple scintillation materials20 adapted to measure different radioisotopes may be used. In anotherembodiment of a measurement sensor 11, scintillation materials 20 thatdo not require the use of a light detector 21 may be used. In anotherembodiment of a measurement sensor, multiple scintillation materials 20,each with their own detection circuitry, may be included to enable a twodimensional array of measurements.

In an embodiment of measurement sensor 11, the light detector 21 mayinclude a signal amplifier 33 or amplification circuitry to handle lowlevel signals. In another embodiment, measurement sensor may furtherinclude a temperature sensor 36 which is coupled to a temperaturecompensator 50, the temperature sensor adapted to measure an ambient orlocal temperature of the scintillation material 20 and light detector21, and to communicate or report such temperature to temperaturecompensator 50. Temperature compensator 50 being adapted to generate atemperature correction factor based on comparison of the ambienttemperature to a reference temperature. The temperature compensator 50may apply the correction factor to the signal data to producetemperature compensated signal data, or may be adapted to reporting thelocal temperatures of the scintillation material 20 and light detector21. Depending on the embodiment, in vivo detection may not requiretemperature compensation in that the measurement sensor 11 might becalibrated for normative subject temperatures. Additionally, someembodiments of the measurement sensor 11 could include temperatureresponse calibration, which would nullify the impact of temperature onsystem 10 operation. This nullification could be accomplished, forexample, by measuring the response a sensor 11 has with respect totemperature, and then modifying the parameters of amplifier 33 or othercircuit components so as to counteract this temperature response.

In another embodiment of the system, a measurement sensor 11 can be, forexample, a device comprising a scintillation material 20; a lightdetector 21 and associated signal amplifier 33 or amplificationcircuitry and sensor processor 22 located on a printed circuit board 23Pin the sensor portion of the system. Light detector 21 may be selectedbased on the application, such as a photodiode or photocathode, andsignal amplifier 33 (or amplification circuitry, possibly incorporatedinto circuit board 23P) may include a photomultiplier or simply a signalamplifier 33. Other associated circuitry may then then moved to themeasurement control device 12. In any number of embodiments, themeasurement sensor 11 can be provided with microelectromechanicalmachine (MEMS) power generation capability such that a battery orexternal power source is not necessary. A MEMS generator may bepiezoelectric based, adapted to generate electricity from a motion ofthe subject 5, body heat of the subject 5, or the blood pressure ofsubject 5. Alternatively, sensor power supply 32 may be a corded powerconnection to either the control device. In another embodiment, ameasurement sensor 11 can be a wireless, with an independent powersupply 32.

In an embodiment of a measurement sensor 11, for example, theelectronics may be enclosed in a light-proof enclosure or housing 25 andthere can be a multi-conductor cable 24 for data communications.Mechanical design of the housing 25 can be used to accurately controlthe placement of the scintillation material 20. As shown in FIGS. 57 and58 , in any number of embodiments, the sensor housing 25 could includestructure for placement and alignment of backscatter material 82.

In an embodiment of a measurement sensor 11, the sensor may includesensor housing 25 which optionally may incorporate a shielding mask 38for collimation of the incoming radiation for increased directionalsensitivity or a backscatter material 82 for the reflection of incomingradiation which is not captured by the scintillation material 20. Theshielding mask 38 can be made of any number of dense materialsincluding, but not limited to: lead, steel, iron, aluminum, iridium,platinum, copper, cement, dense plastic, etc. The shielding mask 38 canbe tailored to protect against specific radiation depending on theapplication of the system of the present invention. As described above,sensor housing 25 may include structure for the placement and alignmentof backscatter material 82.

In an embodiment of a measurement sensor 11, for example, the sensorcould further include a removable and/or disposable protective sleeve orcase, also referred to as carrier 35. This sleeve or carrier 35 can haveadhesive (e.g., adhesive 35A) applied in order to attach the measurementsensor 11 to a test subject 5. This sleeve can also be used as asanitary barrier between the measurement sensor 11 and a test subject 5.In some embodiments, measurement sensor 11 may further include housing25 which itself has adhesive used to attach the sensor 11 to a testsubject 5. Some embodiments of sensor 11 may include structure forattachment, such as an arm band, to the arm of a subject 5. Such an armband may include hook and loop fasteners or other approaches of securingto subject 5. An embodiment may include a pocket or other structure bywhich sensor 11 is secured to the attachment structure or arm band.

In any number of embodiments, measurement sensor 11 and measurementcontrol device 12 may include the necessary hardware and software toenable wireless communications between them. In such an embodiment,encryption techniques may be used to provide security for wirelesssignals.

In any number of embodiments of the system of the present invention, anindividual measurement sensor can be calibrated for radiationsensitivity. This calibration can overcome measurement inconsistenciesdue to manufacturing and physical tolerances in the sensor. Since eachmeasurement sensor 11 has unique manufacturing and physical tolerancesand material characteristics, no two sensors will naturally report thesame measurement given the same radiation source input. Therefore, eachsensor may be exposed to a known activity radiation source and acorrection factor can then be provided for each individual sensor. As aresult, each measurement sensor 11 used in the system 10 may becalibrated with one another with regard to radiation sensitivity.

In any number of embodiments, an individual measurement sensor 11 may becalibrated for temperature sensitivity. Various components of ameasurement sensor 11 are sensitive to temperature changes and thereported radiation activity due to temperature. It is known that ascintillation crystal or material 20, a light detector 21, and, to alesser degree, amplifiers used for light detection, for example, may besensitive to temperature. Therefore, a precision temperature sensor 36may be placed locally or proximally to the temperature sensitiveelements. Ambient temperature can then be recorded during the datacollection process so that corrections or compensation can be made tosignal data or measurement readings in order to compensate for anyinaccuracies in the measurement readings resulting from certainelements' sensitivity to temperature, producing temperature compensatedsignal data. In order to determine temperature correction factors, ameasurement sensor 11 may be subjected to a stable radiation test sourcewhile the surrounding temperature is swept through the range of theoperating temperatures. This may be accomplished in a laboratorytemperature chamber. Through this test process, radiation activity of aknown, stable source as well as temperature data can be recorded. Acalibration curve can then be calculated which adjusts the measuredradiation activity to a normalized flat response corresponding toexpected compensated signal data. Additionally, some embodiments ofsensor 11 may include temperature response calibration, which couldnullify the effect of temperature on system operation. Nullificaton maybe accomplished by measuring the response a senor 11 has with respect totemperature, and then modifying the parameters of amplifier 33 or othercircuit components to counteract this temperature response.

In another embodiment, a measurement sensor 11 may provide adaptiveperformance and measurement capabilities. For example, if the rate oftumor growth accelerates, the sensor can automatically respond to thechange by increasing sampling frequency.

In any number of embodiments of the system, a measurement control device12 can be, for example, a hand-held and battery powered devicecomprising a display screen, a keypad and data communicationsconnectors. An alternative embodiment may include the measurementcontrol device 12 and one or more sensors 11 contained within the samehousing, and operably engaged with wires, printed circuit board tracesetc. In an alternative embodiment of the system of the presentinvention, the measurement control device 12 can be a desktop-stylepowered device. In another embodiment, the measurement control device 12or other portions of system 10 may include a cradle-style charging dockfor the battery operated device. The cradle-style charging dock cancharge batteries for a hand-held device and can also initiate thecapture of any measurements in the hand-held device's memory. In anotherembodiment, the measurement control device 12 may provide MEMS powergeneration capability such that a battery or external power source isnot necessary.

In any number of embodiments of the system 10, as shown in FIGS. 20through 21 for example, a measurement control device 12 comprises acontrol processor 42, control software 56 (optionally as embeddedsoftware), control memory 40, a real-time clock 48, and other associatedlogic and circuitry on a printed circuit board. The control processor 42may be embedded in the measurement control device 12, provided as anexternal processor, or optionally merged with station 70. The controlprocessor 42 is generally specially configured to satisfy embodiments ofthe system 10. The control device can control user-interface, datacollection, and data transmission activities. There are variousmicroprocessors capable of this including small embedded processors andsingle-board computers. FIG. 21 is a flow diagram illustrating operationof an embodiment of a measurement control device 12. The system 10generally may respond to user input, keep track of sensor attachment orassociation, monitor operational parameters, such as battery level, andtransfer measurement data to a desired storage, such as an externalcomputer. In an embodiment of a measurement control device 12, asillustrated in FIG. 20 for example, there can be multiple datacommunications connectors to enable the attachment of multiplemeasurement sensors 11, as well as a data communication to a variety ofdesired storage devices or networks.

In an embodiment of a measurement control device 12, the device canfurther include network connectivity and control hardware and softwareto incorporate the functionality of the control computer software 56.This creates a stand-alone system at the test site which eliminates theneed for a separate computer or computer software. Encryption anddecryption methods known in the art can be provided in any number ofembodiments to secure wireless communications.

An embodiment of a measurement control device 12 may further include abar code scanner for recording pertinent identification numbers,calibration codes, etc. when printed on bar codes. An embodiment of ameasurement control device 12 can further include a pulse-oxygen, skinresistivity, or other biological sensor in order to incorporateadditional data into the measurements collected. Another embodiment of ameasurement control device 12 can further include a digital camerasystem for incorporating photos into the data record file. These photoscould be used for sensor placement details, for example. One embodimentof a measurement control device 12 can further include functionalitywhich communicates to the user specific details pertinent to the test ortest subject being worked with. This communication can include, but isnot limited to, non-standard placement locations for the measurementsensors 11, reminders of tumor size and location, general notes, testrelated photos, etc.

In an embodiment of a measurement control device 12, for example, apower switch can control power to all components of the device, exceptpossibly a real-time clock 48. The clock 48 may have consistent back-uppower to avoid losing the programmed date and time. When the powerswitch is in the “ON” configuration, power may be applied to the devicecomponents, and a microprocessor can start operation and testoperability. The microprocessor of control processor 42 may further testexternal peripherals such as the display 44, the real-time clock 48,etc. As the tests are performed, a display screen of the measurementcontrol device 12 may display, for example, a waiting message. Next, atleast one measurement sensor 11 may be attached to the control device 12via a connector and a cable, such as multiconductor cable 24. Uponattachment of a measurement sensor 11, the control device 12 recognizesthe attachment and performs duties described below to start up themeasurement sensor 11.

In an embodiment of a measurement sensor 11, for example, power may besupplied to the sensor via the measurement control device 12. Forexample, a multi-conductor cable 24 with a connector on the end or aplug that fits into a mating jack can be used to connect the measurementsensor 11 to the control device 12. Power can be supplied to themeasurement sensors 11 over this cable from the measurement controldevice 12. The sensors can be connected to the measurement controldevice 12 before data collection and remain connected throughout datacollection. In another embodiment, the measurement sensor 11 may includeits own sensor power source 32 and non-transient sensor memory 30 tostore recorded data such that no cable might be necessary and the sensordoes not need to remain connected to the measurement control device 12during operation. In order to retrieve the recorded data, wirelesscommunications may be enabled and/or a cable may be connected to themeasurement control device 12 at a desired time.

After power is turned on to the sensor 11, as shown in FIGS. 17 and 21for example, the sensor processor 22 may start operation and testitself. If the self-test verifies that the measurement sensor 11 isoperational, the sensor can alert the measurement control device 12 thatthe measurement sensor 11 is operational and ready to receive an addresswhich is an address that the control device 12 will use to communicatewith the identified measurement sensor 11. The measurement controldevice 12 can next send the measurement sensor 11 a unique address oridentifier 16 assignment (i.e., unique being sufficiently individualizedfor the application to avoid confusion). After receiving the uniqueidentifier 16 assignment, the measurement sensor 11 can accept theunique address and listen to a communications bus for commands specificto the individual sensor. A measurement control device 12 may send anyof the following commands to any of its connected sensors: (1)connection check using the sensor's unique address; (2) Sensor LEDon/off; (3) Set sensor PWM output; (4) Read/Write sensor EEPROM; (5)Measure Temperatures; and/or (6) Measure Radiation pulses for a set timeperiod (for example, one second). Other commands not specifically listedcan be sent by the measurement control device 12. After the measurementcontrol device 12 sends a command to the measurement sensor 11, thesensor performs the commanded action and replies with a result ifnecessary.

In any number of embodiments of the system, when one or more measurementsensors 11 are attached to a measurement control device 12 and thesensors are operational, the measurement control device 12 can indicate,through a message on the display screen, for example, that the device isready to begin data collection. When a user begins data collection, themeasurement control device 12 first downloads each sensor's individualcalibration data and stores the calibration data into control memory 40or other desired memory or storage. The control device 12 can thenrequest for a measurement of temperature and radiation pulses, forexample, from each attached measurement sensor 11. All received readingscan be stored, along with a time stamp, in the control memory 40. Whenthe control memory 40 might be full or if the user stops the datacollection, the measurement control device 12 may simply stop acceptingreadings from the measurement sensors 11. A user may download the saveddata collected from the control memory 40 to a computer or other desiredstorage.

In any number of embodiments, computer program code used in the systemmay be capable of: (1) performing diagnostic tests on the measurementcontrol device 12; (2) transferring measurement data from themeasurement control device and saving it to a record file; (3) gatheringancillary test data from the user or other sources (radiation doseadministered, test subject weight, PET scan data, etc.) and including itin the data record file; (4) transferring the data record file to thedatabase server control software; and (5) calculating the likelihood ofan improperly performed radioactive analyte injection and reporting ordisplaying the same to a user, whether by audible, visual, or othersignal. In any number of embodiments, database server control softwarecan accept incoming data record files from the computer software andapply one or more algorithms to the data received. Measurement data maybe stored in an optional central database 75 while the algorithm outputcan be used to generate reports for the user. These reports can indicateestimated parameters or even estimated future parameters of a tumor.

In an embodiment of the system, for example, a user may attach ameasurement control device 12 to a computer and run computer software totransfer measurement data stored on the measurement control device 12 tothe computer. The computer software or program code communicates withthe control device 12 to determine what type and how much data isavailable for downloading. The computer software can ask the user forpertinent test-related information such as radiation dose administered,identification or number of test subject 5, placement locations of thesensors, tumor location and type, etc. Once measurement data has beentransferred from the measurement control device 12 to the computer, adata record file can be built. Once complete, the data record file canbe transferred to a database server and predictive model or algorithmsystem.

In any number of embodiments, pre-processing operations may be performedon a test subject data set. Session measurements for all channels can benormalized with respect to injected radiation dose, for example. Thedose is recorded during the test and is used to adjust measurements on ascalar basis. A session is one specific data recording event whichincludes sensor placement on the subject 5, injection of radioactivematerial, and collection, recordation and transfer of recorded data.Measurements from each session can be aligned so that the rising edge ona “trigger” channel—right or left arm—is at time zero. The term“trigger” channel is used to mean a sensor that is sure to see a largeamount of radioactive material so that it is ensured to have a dramaticand easily recognizable increase in the measurement. Having a rapidlychanging “step” like this allows for time-alignment of data setsrecorded at different times or “sessions.” Any data which is before apredetermined time or after the predetermined time (for example, databefore time −120 seconds or after time 3600 seconds) can be removed fromthe measurement data. In addition, session measurements for all channelscan be normalized with respect to temperature sensitivity. Individualsensor's temperature correction coefficients can be retrieved and usedto correct the radiation pulse count measurements.

In any number of embodiments of the system, session measurements for allchannels can also be adjusted to account for the natural decay of theradioisotope used, for example. The radioisotope naturally decays in thetest subject and this adds a decreasing function to the measurementdata. Accounting for this natural decay and removing any data attributedto the natural decay can portray the data as the amount of radiationencountered without the decay function included.

In any number of embodiments of the system 10, measurements may bealigned with respect to the control channel(s). Control channels arestable and repetitive, therefore aligning all channels will makedifferences in the non-control channels visible.

In one embodiment of the system 10, a database server and predictivemodel may be provided. A hardware server which runs software toincorporate incoming data record files from the computer software and tosave this incoming data to a database file along with data previouslysaved; and database server control software. FIGS. 14 and 15 , forexample, illustrate flow diagrams of operation of an embodiment of thecomputer software and the database server control software respectively.The database server and predictive algorithm system or model can applyone or more algorithms to this saved database in order to estimateparameters specific to the tumor under test or a group of tumors.Additionally, the database server control software can apply one or moremodels or algorithms in order to predict future parameters of the tumoror a group of tumors. The database server control software can also usethe output of the algorithms to generate report files for the user whichpresent the estimated and/or predicted parameters.

In an alternative embodiment of the system 10, a database server andpredictive model comprises a dynamic website with server softwarerunning behind it, which allows for a multiple-user system for analysisand reporting. In another embodiment, the database server and predictivemodel or algorithm system further includes functionality which transfersthe algorithm output and report back to the computer software foranalysis and interpretation by the user. In one embodiment, the databaseserver and predictive model further includes functionality which canprovide real-time communication and updates about sensor data;notification parameters (e.g., situations with tumor development);and/or alert conditions.

In an alternative embodiment of the system 10, database server controlsoftware keeps a database of all measurement data that has beensubmitted previously. Any new data record files that are submitted canbe added to the database. The user can include other data records suchas, but not limited to, results from other tests (PET Scan, CT Scan,etc.), information about a particular subject (height, weight, etc.), orgeneral notes, for example. The user can use the database server controlsoftware to generate graphs of measured data, to calculate variousfunctions of the measured data and then graph those functions ifnecessary; and/or to apply prediction algorithms to the data. Theprediction model may be capable of, although not limited to: (1)predicting the future outcome of tumor treatments; (2) predicting whichtumor treatments have the best chance of success; (3) predicting thelikelihood that metastatic disease is present in the subject; and/or (4)other. The database server control software can generate reports for theuser of measured data and/or predictions based on the data. Thesereports include, but are not limited to, graphs, predictions withconfidence levels, etc.

In any number of embodiments of the system of the present invention, theclass of algorithms used is of the classification structure in machinelearning. These algorithms use a training set of data to build a modelof the data. Then, when new unknown data sets are introduced, thealgorithms can determine where in the model the new data should fit.This approach allows for the system of the present invention to inspecta submitted data set and determine whether and how closely it has seenexamples like the submitted data set in the past. If there have beensimilar examples in the past, the system can predict the outcome of thecurrent data set based on the outcomes of the past data. For example, ifthere are various past examples that closely match the new datasubmitted, the algorithm can determine which treatments in the past ledto the most favorable outcome. Physicians may then select treatmentswith the best outcome. In another embodiment, the algorithms can provideadaptive performance and measurement capabilities. For example, if therate of tumor growth accelerates, the system can automatically respondto the change by increasing sampling frequency.

In an embodiment of the system 10, the ways in which new data submittedis matched to previously seen data or determined not to match any of theprevious data are based on multiple mathematical or quantitativefunctions that can be applied to measurement data. For example, areaunder the curve, polynomial curve fit to a portion or all of the data,the ratio of two data measurement channels, etc., are all ways in whichdata sets can be matched.

Returning to the figures, FIG. 27 illustrates a detail of an embodimenthighlighting arm band 78, with fasteners 79, such as hook and loopfasteners. Such an embodiment may combine measurement sensor andcontroller on arm band 78. FIG. 28 is another embodiment combined witharm band 78, with measurement sensor 11 and cable 24. FIG. 29illustrates a detail of light shield 28 with light shield sealant 81.

FIG. 30 is a perspective exploded view of an aspect of an embodiment,with light shield 28 having or defining light shield scintillationcavity 28A and detector cavity 28B. Scintillation crystal 20 and lightdetector 21 may thus fit within these cavities, protected by lightshield sealant 81. FIG. 31 is another view of an embodiment of lightshield 28, illustrating light shield sealant 81 and optional collimatoralignment light or LED 85. FIG. 32 is a cutaway of FIG. 31 illustratingan embodiment with relative positioning of scintillation crystal 20,light detector 21 within light shield 28. FIG. 33 is a further explodedview of that embodiment, showing the interrelation of the individualcomponents, with collimator alignment light 85.

FIG. 34 illustrates an embodiment of measurement controller 12, withcommunication link 7, a plurality of controller communications ports 47and optional controller daisy chain port 46. FIG. 35 shows two daisychained controllers.

FIG. 36 shows an embodiment of measurement sensor housing 25, with cable24. FIG. 37 is an external view of another embodiment of measurementsensor housing 25, with light shield 28 and sensor circuit board 23.FIG. 38 is a partial exploded view of the FIG. 37 embodiment,illustrating light detector 21 and scintillation material 20 withrespect to light shield 28 and sensor housing 25. FIGS. 39 and 40 showdifferent sides of an embodiment with a radiation shield alignmentdevice 87 and collimator alignment device 85. FIG. 41 illustratesradiation shield 84. FIGS. 42-43 show details of radiation shield 84. InFIG. 44 is an external bottom side view of an embodiment of measurementsensor 11 with radiation shield 84, with FIG. 45 showing an explodedview of the same embodiment with components separated.

FIG. 46 is a cutaway view of an embodiment of measurement sensor 11attached to a radiation shield 84 defining a collimator, withscintillation material 20 and light detector 21. FIG. 47 is a cutawayview of another embodiment of measurement sensor 11, illustratingoptional collimator alignment device 85. FIG. 48 is a further cutawayview of an embodiment with a different configuration for collimatoralignment device 85.

FIG. 49 is a perspective view of an embodiment of measurement sensor 11with measurement sensor stand 83. FIG. 50 is a closer view of theembodiment of FIG. 49 . FIGS. 51-52 show two different perspective viewsof an embodiment detail with optional radiation shield adjustment legs97.

FIG. 53 illustrates an aspect of some embodiments, with two measurementsensors 11 daisy chained with cable 24. FIG. 54 is another embodiment inwhich a secondary measurement sensor 11 is daisy changed to a primarymeasurement sensor 11 having shielding mask 84. FIG. 55 illustratesvarious form factors for specific embodiments of measurement sensor 11having specific applicability. FIG. 56 is an embodiment with an optionalsensor trigger pushbutton 86.

FIG. 57 is a cutaway view of measurement sensor 11, highlightingbackscatter material 82. FIG. 58 details structure of measurement sensorhousing 25 serving as structure for backscatter materials 82.

Some system 10 embodiments may be directed to the ex vivo real-timedetection of gamma radiation emitted by a subject from administrationand uptake over a period of time of a radioactive analyte that decays invivo by positron emission. These systems 10 may include at least one exvivo measurement sensor 11, at least one computer processor 42 (whichmay or may not be the same as computer/processing station 70) having anon-transient memory 40 and a clock 48, the computer processor 42 inoperable communication with the measurement sensor 11, a temperaturecompensator 50, and computer program code. An ex vivo measurement sensor11 may have a sensor housing 25, a scintillation material 20, a lightdetector 21, a temperature sensor 36, a signal amplifier 33, and asensor power source 32 (whether corded, battery, solar, etc.). The lightdetector 21, temperature sensor 36, signal amplifier 33, and sensorpower source 32 may generally be in operable communication. Thescintillation material 20 and light detector 21 may be disposed withinthe sensor housing 25 in a light proof manner, with the scintillationmaterial 20 adapted to receive a level of gamma radiation over theperiod of time from the in vivo radioactive analyte and to emit photonsrepresentative of the gamma radiation level. The light detector 21 maybe disposed with respect to the scintillation material 20 so as toreceive and convert the photons into signal data representative of thefrequency level over time of gamma radiation received. The signalamplifier 33 may be adapted to amplify the signal data, the measurementsensor 11 having at least one sensor output for such amplified signaldata.

The at least one computer processor 42 may include a non-transientmemory 40 and a clock 48, with the computer processor 42 being inoperable communication with the measurement sensor 11. The memory 40 mayhave control computer program code executable by the at least onecomputer processor 42. The control computer program code may include anumber of software modules, such as a first module 61 for measurement, asecond module 62 for data management.

An optional temperature compensator 50 may be coupled with thetemperature sensor 36, such that the temperature sensor 36 is adapted tomeasure an ambient temperature. The system 10 may thus be adapted tocommunicate the ambient temperature to the temperature compensator 50,so that the temperature compensator 50 may generate a temperaturecorrection factor based on comparison of the ambient temperature to areference temperature. The temperature compensator 50 further adapted toapply the temperature correction factor to the signal data to producetemperature compensated signal data.

The first module 61 may be adapted to receive the signal data in arecord file format, and the second module 62 may be adapted to receivethe signal data of a record file from the first module 61 and totransmit the compensated signal data to a desired storage. The computerprogram code 56 may further include a third module 63 adapted to receivestored data of a record file from the second module 62, and to applysuch stored data to calculate changes in the compensated signal dataover a desired period. This module may also apply stored data to apredictive model to generate predictive data values over a desiredperiod for such record file as a predictive outcome, and to transmitsuch changes to a desired storage, such as database storage 75.

Optionally, the ex vivo measurement sensor 11 may include a radiationshielding mask 84 for gamma radiation. The shielding mask 84 may definean aperture in the form of a collimator 84 c for gamma radiationincident into the scintillation material 20. An alignment feature 87 maybe included for removable alignment of the measurement sensor 11 withrespect to the subject 5. In some cases, the alignment feature 87 mayinclude a light emitter 85 disposed within the sensor 11 so as permitalignment of the collimator aperture 84 c to a desired portion of thesubject 5 by illumination of the subject 5. Optionally, the lightemitter 85 may be a light emitting diode (LED) disposed within theaperture, and optionally the ex vivo measurement sensor 11 may furtherinclude light proof sealant 81 about the LED 85 to prevent the output ofthe diode or ambient light to strike the scintillation material 20,while permitting the scintillation material 20 to receive incident gammaradiation.

Optionally, the ex vivo measurement sensor 11 may further include aradiation shielding mask 84 for gamma radiation, with the shielding maskdefining an aperture in the form of a collimator 84 c for gammaradiation incident into the scintillation material 20; and the system 10may further provide a stand 83 as alignment feature 87 for the removablemounting of the ex vivo measurement sensor 11 in a configurationrelative to the subject 5 so as to permit alignment of the collimator 84c aperture to a desired portion of the subject 5.

Optionally, the third module 63 may detect infiltration conditions. Inone approach, the third module 63 calculates changes in the compensatedsignal data in order to determine infiltration of radioactive analyte.In another approach, the predictive model includes data representativeof radiation frequency over time associated with infiltration of theanalyte within the subject for determining an infiltration. Such apredictive model may include data representative of spike of radiationfrequency over time associated with administration of the analyte fordetermining proper administration of the analyte. An alarm or indicatormay be included to announce the determination of infiltration. Alsooptionally, some embodiments may include an arm-band 78 for removableaffixation of the ex vivo measurement sensor 11 to an arm of the subject5.

Optionally, a filter in noise reduction 37 may be included for filteringthe amplified signal data based on amplitude. Such a filter may beimplemented with a voltage comparator. Alternatively, the filter maycomprises an analog to digital converter and control computer programcode adapted to compare digital amplified signal data to a referencelevel.

A further system 10 embodiment may also be directed to the ex vivoreal-time detection of gamma radiation emitted at an area of interest bya subject from administration and uptake over a period of time of aradioactive analyte that decays in vivo by positron emission. Such anembodiment may include a primary ex vivo measurement sensor 11 and asecondary ex vivo measurement sensor 11. The primary ex vivo measurementsensor 11 may include a sensor housing 25 with a radiation shield 84,the sensor housing 25 with the radiation shield 84 defining a cavity,the radiation shield 84 further defining an aperture into the cavity asa collimator 84 c disposed within the aperture so as to admit acollimated gamma radiation into the cavity from the area of interest, ascintillation material 20 disposed within the cavity such that thecollimated gamma radiation is incident on the scintillation material 20,a light detector 21 disposed within the sensor housing 25 to detectlight emitted from the scintillation material 20, a temperature sensor36, a signal amplifier 33, and a sensor power source 32. The lightdetector 21, temperature sensor 36, signal amplifier 33, and sensorpower source 32 in operable communication.

In general, the scintillation material 20 and light detector 21 may bedisposed within the sensor housing 25 with the scintillation material 20adapted to receive a level of gamma radiation over the period of timefrom the in vivo radioactive analyte, and to emit photons representativeof the gamma radiation level. As above, the light detector 21 may bedisposed with respect to the scintillation material 20 in a manneradapted to receive and convert the multiplied photons into signal datarepresentative of the frequency level over time of gamma radiationreceived. The signal amplifier 33 may amplify the signal data, and themeasurement sensor 11 may have at least one sensor output (e.g., port27) for such amplified signal data.

In this embodiment, there is a secondary ex vivo measurement sensor 11that is unshielded for measuring background gamma radiation, and acollimator alignment system 87 in operable engagement with the sensorhousing 25 for aligning the collimator 84 c to the area of interest.

A temperature compensator 50 may be coupled with the temperature sensor36, such that the temperature sensor 36 is adapted to measure an ambienttemperature. The system 10 may thus be adapted to communicate theambient temperature to the temperature compensator 50, so that thetemperature compensator 50 generates a temperature correction factorbased on comparison of the ambient temperature to a referencetemperature. The temperature compensator 50 is further adapted to applythe temperature correction factor to the signal data to producetemperature compensated signal data.

The at least one computer processor 42 includes a non-transient memory40 and a clock 48, with the computer processor 42 in operablecommunication with the primary and secondary measurement sensors 11. Thememory 40 may have or store control computer program code 56 executableby the at least one computer processor 42, the control computer programcode 56 may have a first module 61 for measurement and a second module62 for data management. The first module 61 may be adapted to receivethe signal data in a record file format. The second module 62 may beadapted to receive the signal data of a record file from the firstmodule 61 and to transmit the compensated signal data to a desiredstorage (e.g., database storage 75). Also included may be third andfourth modules 63, 64 of computer program code 56, the third module 63adapted to receive stored data of a record file from the second module,(i) to apply such stored data to a predictive model to generatepredictive data values over a desired period for such record file as apredictive outcome, and to transmit such predictive outcome to a desiredstorage; and (ii) to apply such stored data to calculate changes in thecompensated signal data over a desired period, and to transmit suchchanges to a desired storage and the fourth module 64 adapted tosubtract signal data from the secondary ex vivo measurement sensor 11from signal data from the primary ex vivo measurement sensor 11 havingradiation shield 84.

This embodiment may include the various options corresponding to theoptions of the foregoing embodiments, though as appropriate, for theshielded primary ex vivo measurement sensor 11. The secondarymeasurement sensor 11 remaining unshielded for the detection ofbackground radiation.

Some embodiments may specifically be directed to the identification ofproper or improper administration of the radioactive analyte to thesubject, including, but not limited to, infiltration, for example. Onesuch embodiment might be a system 10 for the ex vivo real-time detectionover a period of time of gamma radiation emitted by a subject 5 from theadministration of a radioactive analyte that decays in vivo. Theparametric pattern of data (i.e., amplitude, slope, and/or time) fromeither or both proper and improper administration may be used asreference data. The system can compare the amplified signal data of anadministration to this reference data using a parametric model todetermine the probability of proper (or improper) administration of theradioactive analyte to the subject.

In this case, system 10 may include at least one ex vivo gamma radiationmeasurement sensor 11 to detect gamma radiation over a desired period oftime, and to produce signal data associated with the desired period oftime. The ex vivo measurement sensor 11 may be adapted to sensing gammaradiation proximate to a point of administration on the subject 5 of theradioactive analyte. A signal amplifier 33 may be in operablecommunication with the gamma radiation sensor 11 to amplify the signaldata. As above, the measurement sensor 11 may include at least onesensor output or port for communicating such amplified signal data. Thedata may be processed by at least one computer processor 42 in operablecommunication or associated with a non-transient memory 40. Computerprocessor 42 may also be in operable communication with the measurementsensor 11 via its output.

The non-transient memory 40 may have computer program code 56 executableby the computer or controller processor 42 to perform the steps ofreceiving the amplified signal data with the desired period of time,accessing reference data distributed over a reference period of time,comparing the amplified signal data to the reference data using aparametric model to determine the probability of a proper administrationof the radioactive analyte to the subject 5. The computer program code56 may be further adapted to normalize the amplified signal data, andthe parametric model may be a time series function of one or more of theamplitude and slope of the amplified signal data.

Embodiments may extend to a method 100 for the ex vivo real-timedetection over a period of time of gamma radiation emitted by a subjectfrom the administration of a radioactive analyte that decays in vivo, asshown in FIG. 59 . Such a method may include the steps of (i) applying100 an at least one ex vivo gamma radiation measurement sensor 11proximate to a point of administration on the subject 5 of theradioactive analyte; (ii) detecting 120 gamma radiation over a desiredperiod of time and producing signal data associated with the desiredperiod of time; (iii) amplifying 130 the signal data using a signalamplifier in operable communication with the gamma radiation sensor,wherein the measurement sensor having at least one sensor output forsuch amplified signal data and outputting the amplified signal data;(iv) processing 140 the amplified signal data using a computer processorin operative communication with a non-transient memory and themeasurement sensor output by performing the step of: (a) receiving 142the amplified signal data associated with the desired period of time;(b) from the non-transient memory, accessing 144 reference datadistributed over a reference period of time; and (c) determining 146 ifthe administration of the radioactive analyte properly administered theradioactive analyte into the subject by comparing the amplified signaldata to the reference data using a parametric model. Optionally, theprocessing 140 of the amplified signal data may further comprises thestep of normalizing the amplified signal data. The parametric model mayalso be a time series function of one or more of the amplitude and slopeof the amplified signal data.

A system 10 embodiments may include, but are not limited to, an ex vivomeasurement sensor 11 having a sensor housing 25, a scintillationmaterial 20 as a gamma radiation detector or sensor, a light detector21, a signal amplifier 33, and a sensor power source 32. Light detector21, signal amplifier 33, and sensor power source 32 may be in operablecommunication. The scintillation material 20 and light detector 21 maybe disposed within the sensor housing 25 in a light proof manner, withthe scintillation material 20 adapted to receive a level of gammaradiation over the period of time from the in vivo radioactive analyteand to emit photons representative of the gamma radiation level. Thelight detector 21 may be disposed with respect to the scintillationmaterial 20 to receive and convert the photons into signal datarepresentative of the frequency level over time of gamma radiationreceived. The signal amplifier 33 may amplify the signal data, themeasurement sensor 11 having at least one sensor output 27 for suchamplified signal data. At least one computer processor 42 may beassociated with a non-transient memory 40 and a clock 48, the computerprocessor 42 in operable communication with the non-transient memory 40and the measurement sensor 11. The non-transient memory 40 may hold orinclude control computer program code 56 executable by the computerprocessor 42 to receive the amplified signal data in a record fileformat; transmit the amplified signal data to a desired storage; accessreference data from a desired storage; and to apply such amplifiedsignal data to a parametric model to compare the signal data to thereference data to determine the probability of a proper administrationof the radioactive analyte to the subject. As before, the amplifiedsignal data may be normalized, and the parametric model may be a timeseries function of one or more of the amplitude and slope of theamplified signal data.

Amplified signal data resulting from both proper and improperadministrations of radioactive analyte would both include variabilityrelated to the total radioactivity of the radio analyte as well as themethod and process used for the injection. For instance, the injectionspike signal may have varying amplitude depending on the total injectedactivity, or the rate of increase of the amplified signal data wouldchange based on the speed at which the radio analyte is injected.

One approach to account for for the variances caused by the above wouldbe to normalize the amplified signal data based on the maximum amplifiedsignal value recorded. By scaling the amplified signal data such thatits scaled maximum value is, for instance, 1, then various instances ofamplified signal data could be compared against each other even thoughtheir total injected activities may differ. Another method, for example,of normalizing the amplified signal data could be to scale the amplifiedsignal data based on the otherwise measured total activity of theinjected radio analyte.

With respect to the analysis or parametric model that may be done withrespect to the amplified signal data in order to determine thelikelihood or probability that administration of the radioactive analyteis proper (e.g., accurate and consistent with clinical protocol), theparametric model may include various algorithms for comparing theamplified signal data to reference data in order to calculatesimilarities or differences. As noted above, the parametric model may bea time series function of one or more of the amplitude and slope of theamplified signal data.

For the parametric model, one or more representative sets of amplifiedsignal data may be used as references that represent administrations ofradio analyte which were proper, whereas one or more other sets ofamplified signal data could be used as references that representadministrations of radio analyte which were improper. In one embodiment,for example, over a given portion of the amplified signal data, acalculation may be made that would sum the number of seconds duringwhich the amplified signal data is larger than a specified thresholdvalue. For instance, in FIG. 24 , setting a threshold value of 500 wouldcount only the time period between 0 and 10. This desired amount of timethat the amplified signal data is higher than the threshold could becompared to the same algorithm being applied to reference data. Then,the relative similarity or difference in the calculated time ofthreshold crossing would indicate the likelihood or probability that theamplified signal data represents a proper or improper administration ofradio analyte to the subject.

Similarly, in another embodiment of parametric model, instead ofcalculating the time period that the amplified signal data surpasses athreshold, an integral of the amplified signal data during the thresholdsurpassing time period may be calculated. Then, applying this samealgorithm to reference data will, similarly, indicate the likelihoodthat the amplified signal data represents a proper or improperadministration of radio analyte.

Additionally, a parametric model comprising a polynomial could bestatistically fit to the amplified signal data samples so as to providea best fit. The same order polynomial would be fit to reference datasets as well. Then, the polynomial coefficients could be compared inorder to indicate the likelihood that the amplified signal datarepresents a proper or improper administration of radio analyte.

Also, an artificial intelligence neural network or cluster analysisalgorithm could be used as parametric models to compare the amplifiedsignal data to sets of reference data. These algorithms would comparethe amplified signal data to reference data that is known to representproper administrations and to those that are known to represent improperadministrations. The algorithms would then indicate the likelihood thatthe amplified signal data belongs to one of those groups.

It will be apparent to one skilled in the art that a computer systemthat includes suitable programming means or modules for operating inaccordance with the disclosed methods also falls well within the scopeof the present invention. A specially configured computer systemincluding suitable programming means to satisfy the objects describedabove can be provided. Suitable programming means include any means fordirecting a computer system to execute the steps of the system andmethod of the invention, including for example, systems comprised ofprocessing units and arithmetic-logic circuits coupled to computermemory, which systems have the capability of storing in computer memory,which computer memory includes electronic circuits configured to storedata and program instructions, with programmed steps of the method ofthe invention for execution by a processing unit. Aspects of the presentinvention may be embodied in a computer program product, such as anon-transient recording medium, for use with any suitable dataprocessing system. The present system can further run on a variety ofplatforms, including any of a variety of software operating systems.Appropriate hardware, software and programming for carrying out computerinstructions between the different elements and components of thepresent invention are provided.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the claims of the application rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

What is claimed is:
 1. A system for the ex vivo real-time detection overa period of time of gamma radiation emitted by a subject from theadministration of a radioactive analyte that decays in vivo, the systemcomprising: at least one ex vivo gamma radiation measurement sensor todetect gamma radiation over a desired period of time and to producesignal data associated with the desired period of time, the ex vivomeasurement sensor adapted to sensing gamma radiation proximate to apoint of administration on the subject of the radioactive analyte; asignal amplifier in operable communication with the gamma radiationsensor, the signal amplifier adapted to amplify the signal data, themeasurement sensor having at least one sensor output for such amplifiedsignal data; at least one computer processor and a non-transient memory,the computer processor in operable communication with the non-transientmemory and the measurement sensor output port; wherein the non-transientmemory includes computer program code executable by the at least onecomputer processor, the computer program code configured for performingthe steps of receiving the amplified signal data with the desired periodof time and one or more associated patient administration factors,accessing reference data distributed over a reference period of time andone or more associated reference administration factors, and comparingthe amplified signal data and patient administration factors to thereference data and reference administration factors to determine alikelihood of improper administration of the radioactive analyte to thesubject and administration factors associated with improperadministration.
 2. The system of claim 1, wherein the patient orreference administration factors comprise one or more of an identity ofan individual administering the radioactive analyte, a method ofadministration of the radioactive analyte, a dose of radioactive analyteadministered, a type of radioactive analyte, a type of device used toadminister radioactive analyte, an amount of time the device used toadminister radioactive analyte is in place, a needle gauge used toadminister the radioactive analyte, a flush volume used in conjunctionwith the administration of the radioactive analyte, a location ofadministration of the radioactive analyte, an orientation ofadministration of the radioactive analyte, a presence of anautoinjector, a type of patient therapy, and one or more patientcharacteristics.
 3. The system of claim 2 wherein the patientcharacteristics comprise one or more of patient weight, height, age,body-mass index, patient sex, patient hydration, patient movement afterinjection, blood pressure, and blood-glucose.
 4. The system of claim 1further comprising storing administration factors determined to beassociated with a likelihood of improper administrations above athreshold.
 5. The system of claim 4 further comprising an alert to auser when one or more administration factors associated with improperadministrations above the threshold are present.
 6. The system of claim1 wherein the likelihood of improper administration is stored with adiagnostic image associated with the administration of a radioactiveanalyte for reference by a user interpreting the diagnostic image. 7.The system of claim 1 further comprising a determination ofadministration factors associated with a likelihood of improperadministration below a threshold.
 8. A method for the ex vivo real-timedetection over a period of time of gamma radiation emitted by a patientfrom the administration of a radioactive analyte that decays in vivo,the method comprising: (i) identifying one or more patientadministration factors associated with the administration of aradioactive analyte; (ii) applying at least one ex vivo gamma radiationmeasurement sensor proximate to a point of administration on the subjectof the radioactive analyte; (iii) detecting gamma radiation over adesired period of time and producing signal data associated with thedesired period of time; (iv) amplifying the signal data using a signalamplifier in operable communication with the gamma radiation sensor,wherein the measurement sensor includes at least one sensor output forsuch amplified signal data and outputting the amplified signal data; (v)processing the amplified signal data using a computer processor inoperative communication with a non-transient memory and the measurementsensor output by performing the steps of: (a) receiving the patientadministration factors and amplified signal data associated with thedesired period of time; (b) from the non-transient memory, accessingreference administration factors and reference data distributed over areference period of time; and (c) comparing the amplified signal dataand patient administration factors to the reference data and referenceadministration factors to determine a likelihood of improperadministration of the radioactive anal yte to the subject andadministration factors associated with improper administration.
 9. Themethod of claim 8, wherein the patient or reference administrationfactors comprise one or more of an identity of an individualadministering the radioactive analyte, a method of administration of theradioactive analyte, a dose of radioactive analyte administered, a typeof radioactive analyte, a type of device used to administer radioactiveanalyte, an amount of time the device used to administer radioactiveanalyte is in place, a needle gauge used to administer the radioactiveanalyte, a flush volume used in conjunction with the administration ofthe radioactive analyte, a location of administration of the radioactiveanalyte, an orientation of administration of the radioactive analyte, apresence of an autoinjector, a type of patient therapy, and one or morepatient characteristics.
 10. The method of claim 9, wherein the patientcharacteristics comprise one or more of patient weight, height, age,body-mass index, patient sex, patient hydration, patient movement afterinjection, blood pressure, and blood-glucose.
 11. The method of claim 8further comprising the step of storing administration factors determinedto be associated with a likelihood of improper administrations above athreshold.
 12. The method of claim 11 further comprising the step ofalerting a user to the presence of one or more administration factorsassociated with improper administrations above the threshold.
 13. Themethod of claim 8 further comprising the step of storing the likelihoodof improper administration with a diagnostic image associated with theadministration of a radioactive analyte for reference by a userinterpreting the diagnostic image.
 14. The method of claim 8 furthercomprising the step of determining administration factors associatedwith a likelihood of improper administration below a threshold.
 15. Amethod of identifying patient administration factors associated with animproper administration of radioactive analyte to a set of patients, themethod comprising: (i) identifying and collecting a set of patientadministration factors associated with the administration of aradioactive analyte to each patient in the set of patients; (ii)determining, for each patient, whether the radioactive analyte wasadministered properly by performing the steps of: a. applying at leastone ex vivo gamma radiation measurement sensor proximate to a point ofadministration of the radioactive analyte on the patient; b. detectinggamma radiation over a desired period of time and producing signal dataassociated with the desired period of time; c. amplifying the signaldata using a signal amplifier in operable communication with the gammaradiation sensor, wherein the measurement sensor includes at least onesensor output for such amplified signal data and outputting theamplified signal data; d. processing the amplified signal data using acomputer processor in operative communication with a non-transientmemory and the measurement sensor output by performing the steps of: i.receiving the amplified signal data associated with the desired periodof time; ii. from the non-transient memory, accessing reference datadistributed over a reference period of time; and iii. comparing theamplified signal data to the reference data using a parametric model todetermine a likelihood of improper administration, (iii) identifying oneor more patient administration risk factors, wherein patientadministration risk factors comprise patient administration factors thatcorrelate with administrations where the likelihood of improperadministration is above a threshold.
 16. The method of claim 15 whereinpatient administration factors comprise one or more of an identity of anindividual administering the radioactive analyte, a method ofadministration of the radioactive analyte, a dose of radioactive analyteadministered, a type of radioactive analyte, a type of device used toadminister radioactive analyte, an amount of time the device used toadminister radioactive analyte is in place, a needle gauge used toadminister the radioactive analyte, a flush volume used in conjunctionwith the administration of the radioactive analyte, a location ofadministration of the radioactive analyte, an orientation ofadministration of the radioactive analyte, a presence of anautoinjector, a type of patient therapy, and one or more patientcharacteristics.
 17. The method of claim 16 wherein the patientcharacteristics comprise one or more of patient weight, height, age,body-mass index, patient sex, patient hydration, patient movement afterinjection, blood pressure, and blood-glucose.
 18. The method of claim 15further comprising the step of reporting the one or more patientadministration risk factors to a user.
 19. The method of claim 18wherein the user mitigates against the one or more patientadministration risk factors in future patient administrations.
 20. Themethod of claim 15 further comprising the step of identifying one ormore patient administration factors that correlate with administrationswhere the likelihood of improper administration is below a threshold.